20-63346486-G-A

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.*252C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00194 in 664,088 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (5 hom.)
• Consequence: CHRNA4 NM_000744.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.156

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=-0.9).
• BP6: Variant 20-63346486-G-A is Benign according to our data. Variant chr20-63346486-G-A is described in ClinVar as [Benign]. Clinvar id is 1222092.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00153 (233/152256) while in subpopulation NFE AF= 0.00224 (152/68008). AF 95% confidence interval is 0.00195. There are 1 homozygotes in gnomad4. There are 98 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 233 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA4	NM_000744.7	c.*252C>T		3_prime_UTR_variant	6/6	ENST00000370263.9
CHRNA4	NM_001256573.2	c.*252C>T		3_prime_UTR_variant	6/6
CHRNA4	NR_046317.2	n.2345C>T		non_coding_transcript_exon_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA4	ENST00000370263.9	c.*252C>T		3_prime_UTR_variant	6/6	1	NM_000744.7	P1
CHRNA4	ENST00000463705.5	n.2784C>T		non_coding_transcript_exon_variant	5/5	1
CHRNA4	ENST00000631289.1	n.450C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00153 AC: 233 AN: 152138 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00223

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00166 AC: 217 AN: 130622 Hom.: 1 AF XY: 0.00175 AC XY: 125 AN XY: 71288

Gnomad AFR exome AF: 0.000164

Gnomad AMR exome AF: 0.000862

Gnomad ASJ exome AF: 0.00543

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000759

Gnomad FIN exome AF: 0.000742

Gnomad NFE exome AF: 0.00245

Gnomad OTH exome AF: 0.00200

GnomAD4 exome AF: 0.00206 AC: 1054 AN: 511832 Hom.: 5 Cov.: 5 AF XY: 0.00205 AC XY: 570 AN XY: 277818

Gnomad4 AFR exome AF: 0.000201

Gnomad4 AMR exome AF: 0.000813

Gnomad4 ASJ exome AF: 0.00730

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000666

Gnomad4 FIN exome AF: 0.000898

Gnomad4 NFE exome AF: 0.00256

Gnomad4 OTH exome AF: 0.00189

GnomAD4 genome AF: 0.00153 AC: 233 AN: 152256 Hom.: 1 Cov.: 33 AF XY: 0.00132 AC XY: 98 AN XY: 74430

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00224

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00155 Hom.: 1

Bravo AF: 0.00167

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 28, 2020

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	2.0
Dann	Benign	0.45

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: rs113458361; hg19: chr20-61977838;