20-63350191-G-T

Variant names:

• chr20-63350191-G-T
• rs761335733
• NM_000744.7:c.1220C>A

Variant summary

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

The NM_000744.7(CHRNA4):​c.1220C>A​(p.Ser407Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000692 in 1,444,842 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CHRNA4 NM_000744.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.17

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.1220C>A	p.Ser407Tyr	missense_variant	Exon 5 of 6	ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2	c.692C>A	p.Ser231Tyr	missense_variant	Exon 5 of 6		NP_001243502.1
CHRNA4	NR_046317.2	n.1429C>A		non_coding_transcript_exon_variant	Exon 5 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9	c.1220C>A	p.Ser407Tyr	missense_variant	Exon 5 of 6	1	NM_000744.7	ENSP00000359285.4

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD3 exomes AF: 0.00000445 AC: 1 AN: 224516 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 122302

Gnomad AFR exome AF: 0.0000723

Gnomad AMR exome AF: 0.00

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: 6.92e-7 AC: 1 AN: 1444842 Hom.: 0 Cov.: 76 AF XY: 0.00 AC XY: 0 AN XY: 716620

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.00

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.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T;.
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.51	T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Pathogenic	3.2	M;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.61	N;.
REVEL	Benign	0.27
Sift	Benign	0.063	T;.
Sift4G	Benign	0.42	T;T
Polyphen		0.96	D;.
Vest4		0.48
MutPred		0.30		Gain of catalytic residue at S407 (P = 0.0084);.;
MVP		0.81
MPC		1.3
ClinPred		0.65	D
GERP RS		4.7
Varity_R		0.10
gMVP		0.31

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: rs761335733; hg19: chr20-61981543; COSMIC: COSV105921843; COSMIC: COSV105921843;