rs33970119

Positions:

• chr17-4901607-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000080.4(CHRNE):​c.519C>T​(p.Ala173Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0518 in 1,613,756 control chromosomes in the GnomAD database, including 2,544 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (169 hom., cov: 33)
  • Exomes 𝑓: 0.053 (2375 hom.)
• Consequence: CHRNE NM_000080.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.314

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)

CHRNE (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 17-4901607-G-A is Benign according to our data. Variant chr17-4901607-G-A is described in ClinVar as [Benign]. Clinvar id is 128767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4901607-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.314 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNE	NM_000080.4	c.519C>T	p.Ala173Ala	synonymous_variant	6/12	ENST00000649488.2	NP_000071.1
C17orf107	NM_001145536.2	c.*1074G>A		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	c.519C>T	p.Ala173Ala	synonymous_variant	6/12		NM_000080.4	ENSP00000497829.1
C17orf107	ENST00000381365.4	c.*1074G>A		3_prime_UTR_variant	3/3	2	NM_001145536.2	ENSP00000370770.3

Frequencies

GnomAD3 genomes AF: 0.0389 AC: 5917 AN: 152168 Hom.: 169 Cov.: 33

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.0387

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.0366

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0609

Gnomad OTH AF: 0.0392

GnomAD3 exomes AF: 0.0372 AC: 9299 AN: 250084 Hom.: 237 AF XY: 0.0375 AC XY: 5080 AN XY: 135310

Gnomad AFR exome AF: 0.00905

Gnomad AMR exome AF: 0.0241

Gnomad ASJ exome AF: 0.0291

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0106

Gnomad FIN exome AF: 0.0398

Gnomad NFE exome AF: 0.0585

Gnomad OTH exome AF: 0.0419

GnomAD4 exome AF: 0.0531 AC: 77599 AN: 1461470 Hom.: 2375 Cov.: 32 AF XY: 0.0518 AC XY: 37676 AN XY: 727052

Gnomad4 AFR exome AF: 0.00878

Gnomad4 AMR exome AF: 0.0259

Gnomad4 ASJ exome AF: 0.0279

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0103

Gnomad4 FIN exome AF: 0.0399

Gnomad4 NFE exome AF: 0.0623

Gnomad4 OTH exome AF: 0.0491

GnomAD4 genome AF: 0.0388 AC: 5914 AN: 152286 Hom.: 169 Cov.: 33 AF XY: 0.0368 AC XY: 2741 AN XY: 74460

Gnomad4 AFR AF: 0.0109

Gnomad4 AMR AF: 0.0386

Gnomad4 ASJ AF: 0.0291

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.0114

Gnomad4 FIN AF: 0.0366

Gnomad4 NFE AF: 0.0609

Gnomad4 OTH AF: 0.0388

Alfa AF: 0.0505 Hom.: 171

Bravo AF: 0.0391

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.0629

EpiControl AF: 0.0609

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 13, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Congenital myasthenic syndrome Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Congenital myasthenic syndrome 4A Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	13
DANN	Benign	0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs33970119; hg19: chr17-4804902;