rs2273504

Positions:

• chr20-63356709-G-A
• chr20-63356709-G-C
• chr20-63356709-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000744.7(CHRNA4):​c.229-294C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 524,656 control chromosomes in the GnomAD database, including 10,986 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.18 (2880 hom., cov: 33)
  • Exomes 𝑓: 0.19 (8106 hom.)
• Consequence: CHRNA4 NM_000744.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.872

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 20-63356709-G-A is Benign according to our data. Variant chr20-63356709-G-A is described in ClinVar as [Benign]. Clinvar id is 668977.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.454 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.229-294C>T		intron_variant		ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2	c.-318-294C>T		intron_variant			NP_001243502.1
CHRNA4	NR_046317.2	n.413-294C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9	c.229-294C>T		intron_variant		1	NM_000744.7	ENSP00000359285	P1

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28056 AN: 151978 Hom.: 2878 Cov.: 33

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.296

Gnomad AMR AF: 0.212

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.470

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.188

GnomAD4 exome AF: 0.191 AC: 71086 AN: 372560 Hom.: 8106 AF XY: 0.190 AC XY: 37272 AN XY: 196494

Gnomad4 AFR exome AF: 0.170

Gnomad4 AMR exome AF: 0.253

Gnomad4 ASJ exome AF: 0.140

Gnomad4 EAS exome AF: 0.461

Gnomad4 SAS exome AF: 0.164

Gnomad4 FIN exome AF: 0.158

Gnomad4 NFE exome AF: 0.169

Gnomad4 OTH exome AF: 0.184

GnomAD4 genome AF: 0.185 AC: 28070 AN: 152096 Hom.: 2880 Cov.: 33 AF XY: 0.184 AC XY: 13705 AN XY: 74346

Gnomad4 AFR AF: 0.172

Gnomad4 AMR AF: 0.213

Gnomad4 ASJ AF: 0.139

Gnomad4 EAS AF: 0.469

Gnomad4 SAS AF: 0.161

Gnomad4 FIN AF: 0.158

Gnomad4 NFE AF: 0.171

Gnomad4 OTH AF: 0.190

Alfa AF: 0.0559 Hom.: 71

Bravo AF: 0.192

Asia WGS AF: 0.314 AC: 1088 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.7
DANN	Benign	0.47

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: rs2273504; hg19: chr20-61988061; COSMIC: COSV64718173; COSMIC: COSV64718173;