rs763258280

Variant names:

• chr17-4898890-TC-T
• rs763258280
• NM_000080.4:c.1327delG

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PP3_Moderate PP5

The NM_000080.4(CHRNE):​c.1327delG​(p.Glu443LysfsTer64) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000596 in 1,577,704 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: CHRNE NM_000080.4 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:24 O:1
• Conservation: PhyloP100: 7.64

Genes affected

CHRNE (HGNC:1966): (cholinergic receptor nicotinic epsilon subunit) Acetylcholine receptors at mature mammalian neuromuscular junctions are pentameric protein complexes composed of four subunits in the ratio of two alpha subunits to one beta, one epsilon, and one delta subunit. The acetylcholine receptor changes subunit composition shortly after birth when the epsilon subunit replaces the gamma subunit seen in embryonic receptors. Mutations in the epsilon subunit are associated with congenital myasthenic syndrome. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.105 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-4898890-TC-T is Pathogenic according to our data. Variant chr17-4898890-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 1322084.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-4898890-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 243031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4898890-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNE	NM_000080.4	c.1327delG	p.Glu443LysfsTer64	frameshift_variant, splice_region_variant	Exon 12 of 12	ENST00000649488.2	NP_000071.1
CHRNE	XM_017024115.2	c.1291delG	p.Glu431LysfsTer64	frameshift_variant, splice_region_variant	Exon 13 of 13		XP_016879604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNE	ENST00000649488.2	c.1327delG	p.Glu443LysfsTer64	frameshift_variant, splice_region_variant	Exon 12 of 12		NM_000080.4	ENSP00000497829.1
CHRNE	ENST00000649830.1	c.503delG	p.Gly168GlufsTer52	frameshift_variant	Exon 11 of 11			ENSP00000496907.1
CHRNE	ENST00000572438.1	n.1013delG		splice_region_variant, non_coding_transcript_exon_variant	Exon 7 of 7	5
CHRNE	ENST00000652550.1	n.1057-4delG		splice_region_variant, intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152040 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000128 AC: 24 AN: 188070 Hom.: 0 AF XY: 0.000179 AC XY: 18 AN XY: 100644

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000873

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000250

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000652 AC: 93 AN: 1425664 Hom.: 0 Cov.: 34 AF XY: 0.0000921 AC XY: 65 AN XY: 705750

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000783

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000219

Gnomad4 OTH exome AF: 0.0000845

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152040 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74256

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000453

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital myasthenic syndrome 4A Pathogenic:6

Oct 30, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 07, 2022

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A homozygous single base pair deletion c.1267delG in exon 12 of the CHRNE gene that results in a frameshift and premature truncation of the protein 64 amino acids downstream to codon 443 (p.Glu443LysfsTer64) was detected. The observed variation (c.1267delG) has previously been reported in patients affected with congenital myasthenic syndrome and the variant has been classified as pathogenic by ClinVar database. This variant has not been reported in the 1000 genomes database and has a minor allele frequency of 0.15% in the gnomAD . The reference region is conserved across species. -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frameshift variant c.1327del(p.Glu443LysfsTer64) in CHRNE gene has been observed in individual(s) with autosomal recessive congenital myasthenic syndrome (Natera-de Benito D et.al.,2016). Experimental studies have shown that this frameshift affects CHRNE function (Yang Y et.al.,2014). This variant has been reported to the ClinVar database as Pathogenic. The p.Glu443LysfsTer64 variant is reported with allele frequency of 0.01% in gnomAD exomes and novel in 1000 Genomes. This variant causes a frameshift starting with codon Glutamic Acid 443, changes this amino acid to Lysine residue, and creates a premature Stop codon at position 64 of the new reading frame, denoted p.Glu443LysfsTer64. This variant is predicted to cause loss of normal protein function. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -

Mar 24, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 30, 2023

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 05, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change results in a frameshift in the CHRNE gene (p.Glu443Lysfs*64). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 51 amino acid(s) of the CHRNE protein and extend the protein by 12 additional amino acid residues. This variant is present in population databases (rs763258280, gnomAD 0.09%). This frameshift has been observed in individual(s) with autosomal recessive congenital myasthenic syndrome (PMID: 9668239, 10496269, 10514102, 10534268, 27634344). It is commonly reported in individuals of Roma ancestry (PMID: 15322984, 15367858). This variant is also known as c.1267delG. ClinVar contains an entry for this variant (Variation ID: 1322084, 243031). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this frameshift affects CHRNE function (PMID: 10514102). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Congenital myasthenic syndrome 4C Pathogenic:6

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frame shift c.1327del (p.Glu443LysfsTer64) variant in CHRNE gene has been reported previously in homozygous state associated with congenital myasthenia syndrome. This variant has been reported to segregate with autosomal recessive congenital myasthenic syndrome (CMS) in many families. This variant is predicted to cause loss of normal protein function, as the last 51 amino acids are lost and replaced with 63 incorrect amino acids (Croxen, R et al, Natera-de Benito, D et al.). This variant is reported with the allele frequency 0.01% in the gnomAD and novel in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic. This variant causes a frameshift starting with codon Glutamic Acid 443, changes this amino acid to Lysine residue, and creates a premature Stop codon at position 64 of the new reading frame, denoted p.Glu443LysfsTer64. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -

Oct 25, 2017

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 28, 2020

Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 01, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This mutation has been previously reported as disease-causing and was found twice in our laboratory in a homozygous state in individuals with myasthenia. One was as 8-year-old male with congenital myasthenia, with a similarly affected sister (not tested); other was a 15-year-old female with myasthenia gravis, mild intellectual disability. -

not provided Pathogenic:5

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 30, 2016

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 29, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1327delG variant is a common pathogenic variant in individuals of Roma background (PMID: 10534268); Frameshift variant in the C-terminus predicted to result in abnormal protein length, as the last 51 amino acids are lost and replaced with 63 incorrect amino acids; This variant is associated with the following publications: (PMID: 10514102, 10496269, 15367858, 36964972, 15322984, 9668239, 27634344, 28464723, 29056292, 29054425, 30369941, 31589614, 33193787, 34426522, 34008892, 32070632, 31407473, 35175423, 31069529, 10534268) -

Congenital myasthenic syndrome 4B Pathogenic:3

Mar 01, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frame shift c.1327del (p.Glu443LysfsTer64) variant has been reported in homozygous and compound heterozygous state in individuals affected with affected with Congenital Myasthenic Syndrome (Parvizi Omran S et al. 2019; Durmus H et al. 2018). Experimental studies have shown that this frameshift affects CHRNE function (Croxen R et al. 1999). The p.Glu443LysfsTer64 variant has allele frequency 0.01% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submiters). This variant causes a frameshift starting with codon Glutamic Acid 443, changes this amino acid to Lysine residue, and creates a premature Stop codon at position 64 of the new reading frame, denoted p.Glu443LysfsTer64. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -

Feb 23, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.013%). This variant was predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. Multiple pathogenic variants are reported downstream of the variant. This homozygous variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000243031 / PMID: 9668239). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myasthenic syndrome 4C;C4225369:Congenital myasthenic syndrome 4B;C4225413:Congenital myasthenic syndrome 4A Pathogenic:2

Jun 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Suma Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myasthenic syndrome Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Congenital myasthenic syndrome 1A Pathogenic:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frameshift variant c.1327del (p.Glu443LysfsTer64) in CHRNE gene has been reported to segregate with autosomal recessive congenital myasthenic syndrome (CMS) in many families (Natera-de Benito D et.al.,2016). It is a common cause of autosomal recessive CMS in several populations, and has been reported to be a founder mutation in the Roma population (Hantaï D et.al.,2004).This variant has been reported to the ClinVar database as Pathogenic. The p.Glu443LysfsTer64 variant is reported with the allele frequency 0.01276% in gnomAD exomes and novel in 1000 Genomes. This variant causes a frameshift starting with codon Glutamic Acid 443, changes this amino acid to Lysine residue, and creates a premature Stop codon at position 64 of the new reading frame, denoted p.Glu443LysfsTer64. This variant is predicted to cause loss of normal protein function. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.44		Position offset: 0
DS_AL_spliceai		0.90		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs763258280; hg19: chr17-4802185;