rs754133410

Positions:

• chr20-63349876-G-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_000744.7(CHRNA4):​c.1535C>G​(p.Ser512Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000971 in 1,442,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000097 (0 hom.)
• Consequence: CHRNA4 NM_000744.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.72

Genes affected

CHRNA4 (HGNC:1958): (cholinergic receptor nicotinic alpha 4 subunit) This gene encodes a nicotinic acetylcholine receptor, which belongs to a superfamily of ligand-gated ion channels that play a role in fast signal transmission at synapses. These pentameric receptors can bind acetylcholine, which causes an extensive change in conformation that leads to the opening of an ion-conducting channel across the plasma membrane. This protein is an integral membrane receptor subunit that can interact with either nAChR beta-2 or nAChR beta-4 to form a functional receptor. Mutations in this gene cause nocturnal frontal lobe epilepsy type 1. Polymorphisms in this gene that provide protection against nicotine addiction have been described. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25825393).
• BP6: Variant 20-63349876-G-C is Benign according to our data. Variant chr20-63349876-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 568165.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00000971 (14/1442148) while in subpopulation AMR AF= 0.000323 (14/43394). AF 95% confidence interval is 0.000194. There are 0 homozygotes in gnomad4_exome. There are 7 alleles in male gnomad4_exome subpopulation. Median coverage is 83. This position pass quality control queck.
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.1535C>G	p.Ser512Cys	missense_variant	5/6	ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2	c.1007C>G	p.Ser336Cys	missense_variant	5/6		NP_001243502.1
CHRNA4	NR_046317.2	n.1744C>G		non_coding_transcript_exon_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9	c.1535C>G	p.Ser512Cys	missense_variant	5/6	1	NM_000744.7	ENSP00000359285	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000564 AC: 13 AN: 230396 Hom.: 0 AF XY: 0.0000479 AC XY: 6 AN XY: 125286

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000395

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: 0.00000971 AC: 14 AN: 1442148 Hom.: 0 Cov.: 83 AF XY: 0.00000980 AC XY: 7 AN XY: 714526

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000323

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.0000378

ExAC AF: 0.0000249 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal dominant nocturnal frontal lobe epilepsy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 31, 2023

This variant has not been reported in the literature in individuals affected with CHRNA4-related conditions. 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 CHRNA4 protein function. ClinVar contains an entry for this variant (Variation ID: 568165). This variant is present in population databases (rs754133410, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 512 of the CHRNA4 protein (p.Ser512Cys). -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.29	T;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.54	T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.56	N;.
REVEL	Uncertain	0.33
Sift	Benign	0.088	T;.
Sift4G	Benign	0.10	T;T
Polyphen		0.79	P;.
Vest4		0.36
MutPred		0.37		Loss of glycosylation at S512 (P = 0.0112);.;
MVP		0.87
MPC		1.1
ClinPred		0.086	T
GERP RS		2.2
Varity_R		0.042
gMVP		0.37

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: rs754133410; hg19: chr20-61981228;