17-4898816-C-G

Position:

• chr17-4898816-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000080.4(CHRNE):​c.1402G>C​(p.Val468Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00795 in 1,603,472 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0082 (90 hom.)
• Consequence: CHRNE NM_000080.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.492

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0081155).
• BP6: Variant 17-4898816-C-G is Benign according to our data. Variant chr17-4898816-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 128764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4898816-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00558 (849/152282) while in subpopulation SAS AF= 0.0168 (81/4826). AF 95% confidence interval is 0.0138. There are 10 homozygotes in gnomad4. There are 441 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNE	NM_000080.4	c.1402G>C	p.Val468Leu	missense_variant	12/12	ENST00000649488.2	NP_000071.1
CHRNE	XM_017024115.2	c.1366G>C	p.Val456Leu	missense_variant	13/13		XP_016879604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNE	ENST00000649488.2	c.1402G>C	p.Val468Leu	missense_variant	12/12		NM_000080.4	ENSP00000497829.1
CHRNE	ENST00000649830	c.*38G>C		3_prime_UTR_variant	11/11			ENSP00000496907.1
CHRNE	ENST00000572438.1	n.1088G>C		non_coding_transcript_exon_variant	7/7	5
CHRNE	ENST00000652550.1	n.1128G>C		non_coding_transcript_exon_variant	4/4

Frequencies

GnomAD3 genomes AF: 0.00561 AC: 853 AN: 152166 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00752

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0168

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00785

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00753 AC: 1708 AN: 226956 Hom.: 21 AF XY: 0.00863 AC XY: 1058 AN XY: 122620

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00401

Gnomad ASJ exome AF: 0.0139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0198

Gnomad FIN exome AF: 0.000567

Gnomad NFE exome AF: 0.00810

Gnomad OTH exome AF: 0.00697

GnomAD4 exome AF: 0.00820 AC: 11893 AN: 1451190 Hom.: 90 Cov.: 34 AF XY: 0.00866 AC XY: 6243 AN XY: 720800

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00420

Gnomad4 ASJ exome AF: 0.0137

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0202

Gnomad4 FIN exome AF: 0.000899

Gnomad4 NFE exome AF: 0.00808

Gnomad4 OTH exome AF: 0.00886

GnomAD4 genome AF: 0.00558 AC: 849 AN: 152282 Hom.: 10 Cov.: 32 AF XY: 0.00592 AC XY: 441 AN XY: 74456

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00751

Gnomad4 ASJ AF: 0.0147

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0168

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.00782

Gnomad4 OTH AF: 0.00664

Alfa AF: 0.00470 Hom.: 0

Bravo AF: 0.00574

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00687 AC: 59

ExAC AF: 0.00716 AC: 867

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 10, 2014	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 27, 2018	- -

Congenital myasthenic syndrome 4A Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -

Congenital myasthenic syndrome Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 21, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 4C;C4225369:Congenital myasthenic syndrome 4B;C4225413:Congenital myasthenic syndrome 4A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	14
DANN	Benign	0.94
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.57	.;T
MetaRNN	Benign	0.0081	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.0	N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.040	N;.
REVEL	Benign	0.19
Sift	Benign	0.44	T;.
Sift4G	Benign	0.78	T;.
Polyphen		0.0060	B;B
Vest4		0.026
MutPred		0.52		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP		0.74
MPC		0.17
ClinPred		0.0047	T
GERP RS		0.89
Varity_R		0.084
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs139171143; hg19: chr17-4802111;