rs990457690

Variant names:

• chr17-4903158-C-T
• rs990457690
• ENST00000649830.1:c.-887-395G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5 BP4

The ENST00000649830.1(CHRNE):​c.-887-395G>A variant causes a intron change. The variant allele was found at a frequency of 0.00000459 in 1,306,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: CHRNE ENST00000649830.1 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 4.00
• Publications: 1 publications found

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]

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PP5: Variant 17-4903158-C-T is Pathogenic according to our data. Variant chr17-4903158-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 465866.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNE	NM_000080.4	c.-95G>A		upstream_gene_variant		ENST00000649488.2	NP_000071.1
C17orf107	NM_001145536.2	c.*2625C>T		downstream_gene_variant		ENST00000381365.4	NP_001139008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNE	ENST00000649830.1	c.-887-395G>A		intron_variant	Intron 1 of 10			ENSP00000496907.1
CHRNE	ENST00000649488.2	c.-95G>A		upstream_gene_variant			NM_000080.4	ENSP00000497829.1
C17orf107	ENST00000381365.4	c.*2625C>T		downstream_gene_variant		2	NM_001145536.2	ENSP00000370770.3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

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

GnomAD4 exome AF: 0.00000260 AC: 3 AN: 1154590 Hom.: 0 AF XY: 0.00000171 AC XY: 1 AN XY: 584924

African (AFR) AF: 0.00 AC: 0 AN: 26744

American (AMR) AF: 0.00 AC: 0 AN: 39374

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23858

East Asian (EAS) AF: 0.00 AC: 0 AN: 36200

South Asian (SAS) AF: 0.00 AC: 0 AN: 77320

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48874

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4886

European-Non Finnish (NFE) AF: 0.00000354 AC: 3 AN: 847294

Other (OTH) AF: 0.00 AC: 0 AN: 50040

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152082 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74284

African (AFR) AF: 0.0000725 AC: 3 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital myasthenic syndrome 4A Pathogenic:2

Feb 22, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 465866). For these reasons, this variant has been classified as Pathogenic. Adjacent variants within the N-box (c.-94G>A, c.-96C>T) have also been observed to segregate with congenital myasthenic syndrome in affected families (PMID: 10211467, 11960891) and functional studies show that they affect CHRNE expression (PMID: 8663316, 9606190). This suggests that the N-box is important for CHRNE expression, and that other variants in this motif may also be pathogenic. This variant affects a highly conserved nucleotide within the N-box motif of the CHRNE promoter region of CHRNE termed the N-box. Experimental studies show that variants affecting the N-box motif impair DNA-binding efficiency and epsilon subunit transcription, which drives synapse-specific CHRNE expression (PMID: 8663316, 9606190). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This variant is also known as -155G>A. This variant has been observed in individuals with autosomal recessive congenital myasthenic syndrome (PMID: 10382905). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.02%). This variant occurs in a non-coding region of the CHRNE gene. It does not change the encoded amino acid sequence of the CHRNE protein. -

not provided Pathogenic:1 Uncertain:1

Sep 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 06, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Previously reported in an individual with congenital myasthenia syndrome who had a second CHRNE variant; however segregation information was not reported (PMID: 33756069); Published functional studies suggest that the variant is located in a promoter region of CHRNE and results in reduced gene expression (PMID: 8663316); Also known as c.-155G>A; This variant is associated with the following publications: (PMID: 8663316, 33756069, 10382905) -

Congenital myasthenic syndrome 4C;C4225369:Congenital myasthenic syndrome 4B;C4225413:Congenital myasthenic syndrome 4A Pathogenic:1

Jan 18, 2024

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not Provided -

Congenital myasthenic syndrome 4B Pathogenic:1

Dec 12, 2019

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Benign	0.86
PhyloP100		4.0
PromoterAI		-0.12	Neutral

Splicing

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

Other links and lift over

dbSNP: rs990457690; hg19: chr17-4806453;