rs6010918

Positions:

• chr20-63358149-A-G
• chr20-63358149-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000370263.9(CHRNA4):​c.228+1399T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.875 in 152,202 control chromosomes in the GnomAD database, including 59,535 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.87 (59535 hom., cov: 33)
• Consequence: CHRNA4 ENST00000370263.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.204

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.228+1399T>C		intron_variant		ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2	c.-319+1399T>C		intron_variant			NP_001243502.1
CHRNA4	NR_046317.2	n.412+1399T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9	c.228+1399T>C		intron_variant		1	NM_000744.7	ENSP00000359285	P1

Frequencies

GnomAD3 genomes AF: 0.875 AC: 133071 AN: 152084 Hom.: 59507 Cov.: 33

Gnomad AFR AF: 0.665

Gnomad AMI AF: 0.996

Gnomad AMR AF: 0.938

Gnomad ASJ AF: 0.925

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.955

Gnomad FIN AF: 0.979

Gnomad MID AF: 0.946

Gnomad NFE AF: 0.952

Gnomad OTH AF: 0.891

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.875 AC: 133154 AN: 152202 Hom.: 59535 Cov.: 33 AF XY: 0.881 AC XY: 65528 AN XY: 74414

Gnomad4 AFR AF: 0.665

Gnomad4 AMR AF: 0.938

Gnomad4 ASJ AF: 0.925

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.955

Gnomad4 FIN AF: 0.979

Gnomad4 NFE AF: 0.952

Gnomad4 OTH AF: 0.892

Alfa AF: 0.905 Hom.: 7880

Bravo AF: 0.861

Asia WGS AF: 0.962 AC: 3345 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	7.9
DANN	Benign	0.70

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: rs6010918; hg19: chr20-61989501;