rs753828284

Positions:

chr17-4901171-GATGGCCC-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000080.4(CHRNE):c.614_620del(p.Trp205SerfsTer7) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000218 in 1,606,940 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

CHRNE
NM_000080.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 9.32

Variant links:

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]

CHRNE links:

C17orf107 (HGNC:37238): (chromosome 17 open reading frame 107)

C17orf107 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 17-4901171-GATGGCCC-G is Pathogenic according to our data. Variant chr17-4901171-GATGGCCC-G is described in ClinVar as [Pathogenic]. Clinvar id is 18357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4901171-GATGGCCC-G is described in Lovd as [Pathogenic]. Variant chr17-4901171-GATGGCCC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNE	NM_000080.4 linkuse as main transcript	c.614_620del	p.Trp205SerfsTer7	frameshift_variant	7/12	ENST00000649488.2	NP_000071.1
C17orf107	NM_001145536.2 linkuse as main transcript	c.640_646del		3_prime_UTR_variant	3/3	ENST00000381365.4	NP_001139008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNE	ENST00000649488.2 linkuse as main transcript	c.614_620del	p.Trp205SerfsTer7	frameshift_variant	7/12		NM_000080.4	ENSP00000497829	P1
C17orf107	ENST00000381365.4 linkuse as main transcript	c.640_646del		3_prime_UTR_variant	3/3	2	NM_001145536.2	ENSP00000370770	A2

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000372

AC:

AN:

241986

Hom.:

AF XY:

0.0000227

AC XY:

AN XY:

132184

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000719

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.000233

AC:

339

AN:

1454758

Hom.:

AF XY:

0.000203

AC XY:

147

AN XY:

723842

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000301

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000680

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 02, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2022	Published functional studies demonstrate a damaging effect (null allele) (Ohno et al., 1997); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 9158150, 14532324, 31589614) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 11, 2017	- -

Congenital myasthenic syndrome

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	Variant summary: CHRNE c.614_620delGGGCCAT (p.Trp205SerfsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.7e-05 in 241986 control chromosomes. c.614_620delGGGCCAT has been reported in the literature in multiple individuals affected with Congenital Myasthenic Syndrome (example, Ohno_2003). These data indicate that the variant is very likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Dec 01, 2021	- -

Congenital myasthenic syndrome 4A

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 28, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	This sequence change creates a premature translational stop signal (p.Trp205Serfs*7) in the CHRNE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHRNE are known to be pathogenic (PMID: 22678886). This variant is present in population databases (rs753828284, gnomAD 0.009%). This premature translational stop signal has been observed in individuals with autosomal recessive congenital myasthenic syndrome (PMID: 9158150; Invitae). This variant is also known as 553del7. ClinVar contains an entry for this variant (Variation ID: 18357). For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 09, 2021

- -

Congenital myasthenic syndrome 4C

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1997

- -

Congenital myasthenic syndrome 4B

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Dec 31, 2018

This frameshifting variant in exon 7 of 12 introduces a premature stop codon and is predicted to result in loss of normal protein function. This variant has been previously reported as a compound heterozygous or homozygous change in multiple individuals with congenital myasthenic syndrome (PMID: 9158150, 14532324). Segregation analyses of unaffected family members have indicated this variant acts in a recessive fashion (PMID: 14532324). Functional studies performed in HEK cells have shown the c.614_620del (p.Trp205SerfsTer7) variant is a null mutation (PMID: 9158150). This variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.004% (11/273326) and thus is presumed to be rare. Based on the available evidence, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over