17-4899332-G-T

Position:

• chr17-4899332-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000080.4(CHRNE):​c.1085C>A​(p.Ala362Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,401,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A362G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CHRNE NM_000080.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:1
• Conservation: PhyloP100: -0.110

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.085351735).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNE	NM_000080.4	c.1085C>A	p.Ala362Asp	missense_variant	10/12	ENST00000649488.2
CHRNE	XM_017024115.2	c.1049C>A	p.Ala350Asp	missense_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNE	ENST00000649488.2	c.1085C>A	p.Ala362Asp	missense_variant	10/12		NM_000080.4	P1
CHRNE	ENST00000649830.1	c.152C>A	p.Ala51Asp	missense_variant	10/11
CHRNE	ENST00000572438.1	n.771C>A		non_coding_transcript_exon_variant	5/7	5
CHRNE	ENST00000652550.1	n.815C>A		non_coding_transcript_exon_variant	2/4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000647 AC: 1 AN: 154666 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 86132

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000400

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1401912 Hom.: 0 Cov.: 35 AF XY: 0.00000144 AC XY: 1 AN XY: 694070

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000273

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: 9.19e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital myasthenic syndrome 4A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 07, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CHRNE protein function. This variant has not been reported in the literature in individuals affected with CHRNE-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 362 of the CHRNE protein (p.Ala362Asp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	5.9
DANN	Benign	0.56
DEOGEN2	Benign	0.12	T;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.068	N
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.085	T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.27	N;N;.
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.28	N;.;.
REVEL	Benign	0.14
Sift	Benign	0.54	T;.;.
Sift4G	Benign	0.61	T;.;.
Polyphen		0.0	B;B;.
Vest4		0.16
MutPred		0.32		Loss of glycosylation at S367 (P = 0.1688);Loss of glycosylation at S367 (P = 0.1688);.;
MVP		0.66
MPC		0.26
ClinPred		0.026	T
GERP RS		-3.3
Varity_R		0.11
gMVP		0.32

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: rs1053507936; hg19: chr17-4802627;