rs2273502

Positions:

• chr20-63356470-C-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.229-55G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0799 in 1,528,598 control chromosomes in the GnomAD database, including 5,730 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.096 (753 hom., cov: 31)
  • Exomes 𝑓: 0.078 (4977 hom.)
• Consequence: CHRNA4 NM_000744.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.892

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=-0.89).
• BP6: Variant 20-63356470-C-T is Benign according to our data. Variant chr20-63356470-C-T is described in ClinVar as [Benign]. Clinvar id is 1238055.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-63356470-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA4	NM_000744.7	c.229-55G>A		intron_variant		ENST00000370263.9
CHRNA4	NM_001256573.2	c.-318-55G>A		intron_variant
CHRNA4	NR_046317.2	n.413-55G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA4	ENST00000370263.9	c.229-55G>A		intron_variant		1	NM_000744.7	P1

Frequencies

GnomAD3 genomes AF: 0.0962 AC: 14600 AN: 151792 Hom.: 751 Cov.: 31

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.0813

Gnomad AMR AF: 0.0766

Gnomad ASJ AF: 0.0885

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.0873

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.0713

Gnomad OTH AF: 0.105

GnomAD4 exome AF: 0.0781 AC: 107574 AN: 1376688 Hom.: 4977 Cov.: 24 AF XY: 0.0805 AC XY: 54932 AN XY: 682258

Gnomad4 AFR exome AF: 0.145

Gnomad4 AMR exome AF: 0.0543

Gnomad4 ASJ exome AF: 0.102

Gnomad4 EAS exome AF: 0.124

Gnomad4 SAS exome AF: 0.162

Gnomad4 FIN exome AF: 0.0877

Gnomad4 NFE exome AF: 0.0671

Gnomad4 OTH exome AF: 0.0859

GnomAD4 genome AF: 0.0963 AC: 14625 AN: 151910 Hom.: 753 Cov.: 31 AF XY: 0.0972 AC XY: 7220 AN XY: 74258

Gnomad4 AFR AF: 0.134

Gnomad4 AMR AF: 0.0766

Gnomad4 ASJ AF: 0.0885

Gnomad4 EAS AF: 0.130

Gnomad4 SAS AF: 0.164

Gnomad4 FIN AF: 0.0873

Gnomad4 NFE AF: 0.0713

Gnomad4 OTH AF: 0.104

Alfa AF: 0.0838 Hom.: 159

Bravo AF: 0.0949

Asia WGS AF: 0.148 AC: 512 AN: 3476

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 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	12
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2273502; hg19: chr20-61987822; COSMIC: COSV64718293; COSMIC: COSV64718293;