rs762374374

chr20-63350263-C-T

Variant summary

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

The NM_000744.7(CHRNA4):c.1148G>A(p.Arg383His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000552 in 1,610,974 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R383C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: CHRNA4 NM_000744.7 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.61

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06121239).
• BP6: Variant 20-63350263-C-T is Benign according to our data. Variant chr20-63350263-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 476999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000789 (12/152184) while in subpopulation NFE AF= 0.000147 (10/68022). AF 95% confidence interval is 0.0000791. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA4	NM_000744.7	c.1148G>A	p.Arg383His	missense_variant	5/6	ENST00000370263.9
CHRNA4	NM_001256573.2	c.620G>A	p.Arg207His	missense_variant	5/6
CHRNA4	NR_046317.2	n.1357G>A		non_coding_transcript_exon_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA4	ENST00000370263.9	c.1148G>A	p.Arg383His	missense_variant	5/6	1	NM_000744.7	P1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000579 AC: 14 AN: 241762 Hom.: 0 AF XY: 0.0000530 AC XY: 7 AN XY: 132090

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000264

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: 0.0000462

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000528 AC: 77 AN: 1458790 Hom.: 0 Cov.: 99 AF XY: 0.0000455 AC XY: 33 AN XY: 725602

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000270

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000531

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74336

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000997 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000414 AC: 5

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant nocturnal frontal lobe epilepsy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 15, 2022

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 14, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	12
Dann	Uncertain	0.99
DEOGEN2	Benign	0.32	T;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.64	T;T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.061	T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.66	N;.
REVEL	Benign	0.19
Sift	Benign	0.066	T;.
Sift4G	Benign	0.081	T;T
Polyphen		0.0020	B;.
Vest4		0.13
MVP		0.87
MPC		0.50
ClinPred		0.068	T
GERP RS		1.2
Varity_R		0.027
gMVP		0.25

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: rs762374374; hg19: chr20-61981615; COSMIC: COSV64718527; COSMIC: COSV64718527;