rs56069517

chr20-63349887-G-Achr20-63349887-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000744.7(CHRNA4):c.1524C>T(p.Gly508=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,593,084 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (36 hom.)
• Consequence: CHRNA4 NM_000744.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.37

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=-0.55).
• BP6: Variant 20-63349887-G-A is Benign according to our data. Variant chr20-63349887-G-A is described in ClinVar as [Benign]. Clinvar id is 136760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63349887-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.37 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00118 (180/152302) while in subpopulation SAS AF= 0.0151 (73/4828). AF 95% confidence interval is 0.0123. There are 2 homozygotes in gnomad4. There are 118 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 179 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA4	NM_000744.7	c.1524C>T	p.Gly508=	synonymous_variant	5/6	ENST00000370263.9
CHRNA4	NM_001256573.2	c.996C>T	p.Gly332=	synonymous_variant	5/6
CHRNA4	NR_046317.2	n.1733C>T		non_coding_transcript_exon_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA4	ENST00000370263.9	c.1524C>T	p.Gly508=	synonymous_variant	5/6	1	NM_000744.7	P1

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 179 AN: 152184 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0153

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00304 AC: 691 AN: 227220 Hom.: 14 AF XY: 0.00398 AC XY: 493 AN XY: 123784

Gnomad AFR exome AF: 0.000137

Gnomad AMR exome AF: 0.000797

Gnomad ASJ exome AF: 0.000561

Gnomad EAS exome AF: 0.0000573

Gnomad SAS exome AF: 0.0181

Gnomad FIN exome AF: 0.0000529

Gnomad NFE exome AF: 0.00136

Gnomad OTH exome AF: 0.00216

GnomAD4 exome AF: 0.00171 AC: 2461 AN: 1440782 Hom.: 36 Cov.: 83 AF XY: 0.00231 AC XY: 1649 AN XY: 713786

Gnomad4 AFR exome AF: 0.000212

Gnomad4 AMR exome AF: 0.000857

Gnomad4 ASJ exome AF: 0.000672

Gnomad4 EAS exome AF: 0.0000511

Gnomad4 SAS exome AF: 0.0186

Gnomad4 FIN exome AF: 0.0000589

Gnomad4 NFE exome AF: 0.000594

Gnomad4 OTH exome AF: 0.00209

GnomAD4 genome AF: 0.00118 AC: 180 AN: 152302 Hom.: 2 Cov.: 33 AF XY: 0.00158 AC XY: 118 AN XY: 74476

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0151

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00113

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000975 Hom.: 2

Bravo AF: 0.000808

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 17, 2013

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. -

Autosomal dominant nocturnal frontal lobe epilepsy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 03, 2017

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	-0.55
Cadd	Benign	7.3
Dann	Benign	0.40

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: rs56069517; hg19: chr20-61981239; COSMIC: COSV64720703; COSMIC: COSV64720703;