rs1044393

Variant names:

• chr20-63350772-A-G
• rs1044393
• NM_000744.7:c.639T>C

Your query was ambiguous. Multiple possible variants found:

• chr20-63350772-A-G
• chr20-63350772-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000744.7(CHRNA4):​c.639T>C​(p.Asp213Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.862 in 1,613,240 control chromosomes in the GnomAD database, including 604,517 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (47932 hom., cov: 28)
  • Exomes 𝑓: 0.87 (556585 hom.)
• Consequence: CHRNA4 NM_000744.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.395

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 20-63350772-A-G is Benign according to our data. Variant chr20-63350772-A-G is described in ClinVar as [Benign]. Clinvar id is 128749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63350772-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.395 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.875 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.639T>C	p.Asp213Asp	synonymous_variant	Exon 5 of 6	ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2	c.111T>C	p.Asp37Asp	synonymous_variant	Exon 5 of 6		NP_001243502.1
CHRNA4	NR_046317.2	n.848T>C		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.639T>C	p.Asp213Asp	synonymous_variant	Exon 5 of 6	1	NM_000744.7	ENSP00000359285.4

Frequencies

GnomAD3 genomes AF: 0.781 AC: 118258 AN: 151408 Hom.: 47914 Cov.: 28

Gnomad AFR AF: 0.539

Gnomad AMI AF: 0.914

Gnomad AMR AF: 0.861

Gnomad ASJ AF: 0.836

Gnomad EAS AF: 0.870

Gnomad SAS AF: 0.785

Gnomad FIN AF: 0.894

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.881

Gnomad OTH AF: 0.788

GnomAD3 exomes AF: 0.846 AC: 212327 AN: 251030 Hom.: 90951 AF XY: 0.847 AC XY: 115041 AN XY: 135822

Gnomad AFR exome AF: 0.527

Gnomad AMR exome AF: 0.914

Gnomad ASJ exome AF: 0.827

Gnomad EAS exome AF: 0.868

Gnomad SAS exome AF: 0.782

Gnomad FIN exome AF: 0.889

Gnomad NFE exome AF: 0.878

Gnomad OTH exome AF: 0.847

GnomAD4 exome AF: 0.870 AC: 1271958 AN: 1461714 Hom.: 556585 Cov.: 89 AF XY: 0.869 AC XY: 631585 AN XY: 727142

Gnomad4 AFR exome AF: 0.519

Gnomad4 AMR exome AF: 0.908

Gnomad4 ASJ exome AF: 0.824

Gnomad4 EAS exome AF: 0.877

Gnomad4 SAS exome AF: 0.786

Gnomad4 FIN exome AF: 0.889

Gnomad4 NFE exome AF: 0.887

Gnomad4 OTH exome AF: 0.852

GnomAD4 genome AF: 0.781 AC: 118314 AN: 151526 Hom.: 47932 Cov.: 28 AF XY: 0.785 AC XY: 58109 AN XY: 73998

Gnomad4 AFR AF: 0.538

Gnomad4 AMR AF: 0.861

Gnomad4 ASJ AF: 0.836

Gnomad4 EAS AF: 0.869

Gnomad4 SAS AF: 0.786

Gnomad4 FIN AF: 0.894

Gnomad4 NFE AF: 0.881

Gnomad4 OTH AF: 0.791

Alfa AF: 0.825 Hom.: 19739

Bravo AF: 0.769

Asia WGS AF: 0.811 AC: 2821 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 99% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 92. Only high quality variants are reported. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 16, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 24, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autosomal dominant nocturnal frontal lobe epilepsy 1 Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant nocturnal frontal lobe epilepsy Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Jan 08, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.48
DANN	Benign	0.58

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: rs1044393; hg19: chr20-61982124;