20-63346482-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000744.7(CHRNA4):c.*256G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 653,508 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0043 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00086 (2 hom.)
• Consequence: CHRNA4 NM_000744.7 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.72

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 20-63346482-C-T is Benign according to our data. Variant chr20-63346482-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1197461.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00429 (653/152282) while in subpopulation AFR AF= 0.0142 (590/41552). AF 95% confidence interval is 0.0133. There are 5 homozygotes in gnomad4. There are 313 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 650 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA4	NM_000744.7	c.*256G>A		3_prime_UTR_variant	6/6	ENST00000370263.9
CHRNA4	NM_001256573.2	c.*256G>A		3_prime_UTR_variant	6/6
CHRNA4	NR_046317.2	n.2349G>A		non_coding_transcript_exon_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA4	ENST00000370263.9	c.*256G>A		3_prime_UTR_variant	6/6	1	NM_000744.7	P1
CHRNA4	ENST00000463705.5	n.2788G>A		non_coding_transcript_exon_variant	5/5	1
CHRNA4	ENST00000631289.1	n.454G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00427 AC: 650 AN: 152164 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00124 AC: 162 AN: 130558 Hom.: 1 AF XY: 0.00118 AC XY: 84 AN XY: 71268

Gnomad AFR exome AF: 0.0130

Gnomad AMR exome AF: 0.000616

Gnomad ASJ exome AF: 0.00617

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000447

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.000161

Gnomad OTH exome AF: 0.000749

GnomAD4 exome AF: 0.000858 AC: 430 AN: 501226 Hom.: 2 Cov.: 4 AF XY: 0.000790 AC XY: 215 AN XY: 272220

Gnomad4 AFR exome AF: 0.0122

Gnomad4 AMR exome AF: 0.000730

Gnomad4 ASJ exome AF: 0.00626

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000488

Gnomad4 FIN exome AF: 0.000999

Gnomad4 NFE exome AF: 0.000111

Gnomad4 OTH exome AF: 0.00154

GnomAD4 genome AF: 0.00429 AC: 653 AN: 152282 Hom.: 5 Cov.: 33 AF XY: 0.00420 AC XY: 313 AN XY: 74454

Gnomad4 AFR AF: 0.0142

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00291 Hom.: 2

Bravo AF: 0.00476

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	1.8
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: rs45509391; hg19: chr20-61977834;