rs2273504

Variant names:

• chr20-63356709-G-A
• rs2273504
• NM_000744.7:c.229-294C>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 22 publications found

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]

CHRNA4 Gene-Disease associations (from GenCC):

• autosomal dominant nocturnal frontal lobe epilepsy 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• familial sleep-related hypermotor epilepsy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nocturnal frontal lobe epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.229-294C>T		intron_variant	Intron 2 of 5	ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2	c.-318-294C>T		intron_variant	Intron 2 of 5		NP_001243502.1
CHRNA4	NR_046317.2	n.413-294C>T		intron_variant	Intron 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9	c.229-294C>T		intron_variant	Intron 2 of 5	1	NM_000744.7	ENSP00000359285.4

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

African (AFR) AF: 0.170 AC: 1820 AN: 10712

American (AMR) AF: 0.253 AC: 4027 AN: 15896

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 1600 AN: 11416

East Asian (EAS) AF: 0.461 AC: 11426 AN: 24766

South Asian (SAS) AF: 0.164 AC: 7264 AN: 44388

European-Finnish (FIN) AF: 0.158 AC: 3505 AN: 22140

Middle Eastern (MID) AF: 0.152 AC: 239 AN: 1574

European-Non Finnish (NFE) AF: 0.169 AC: 37277 AN: 220282

Other (OTH) AF: 0.184 AC: 3928 AN: 21386

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

African (AFR) AF: 0.172 AC: 7149 AN: 41476

American (AMR) AF: 0.213 AC: 3250 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 483 AN: 3472

East Asian (EAS) AF: 0.469 AC: 2426 AN: 5170

South Asian (SAS) AF: 0.161 AC: 776 AN: 4828

European-Finnish (FIN) AF: 0.158 AC: 1673 AN: 10612

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.171 AC: 11599 AN: 67934

Other (OTH) AF: 0.190 AC: 401 AN: 2108

Alfa AF: 0.180 Hom.: 3036

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

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.87
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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