20-63346482-C-T

Variant names:

• chr20-63346482-C-T
• rs45509391
• NM_000744.7:c.*256G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate 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
• Publications: 2 publications found

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]

CHRNA4 Gene-Disease associations (from GenCC):

• autosomal dominant nocturnal frontal lobe epilepsy 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• familial sleep-related hypermotor epilepsy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nocturnal frontal lobe epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 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 VariationId is 1197461.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 653 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000744.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA4	NM_000744.7	MANE Select	c.*256G>A		3_prime_UTR	Exon 6 of 6	NP_000735.1	P43681-1
	CHRNA4	NM_001256573.2		c.*256G>A		3_prime_UTR	Exon 6 of 6	NP_001243502.1	Q4VAQ3
	CHRNA4	NR_046317.2		n.2349G>A		non_coding_transcript_exon	Exon 6 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA4	ENST00000370263.9	TSL:1 MANE Select	c.*256G>A		3_prime_UTR	Exon 6 of 6	ENSP00000359285.4	P43681-1
	CHRNA4	ENST00000463705.5	TSL:1	n.2788G>A		non_coding_transcript_exon	Exon 5 of 5
	CHRNA4	ENST00000631289.1	TSL:6	n.454G>A		non_coding_transcript_exon	Exon 1 of 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

GnomAD2 exomes AF: 0.00124 AC: 162 AN: 130558 AF XY: 0.00118

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 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

African (AFR) AF: 0.0122 AC: 180 AN: 14702

American (AMR) AF: 0.000730 AC: 24 AN: 32888

Ashkenazi Jewish (ASJ) AF: 0.00626 AC: 116 AN: 18516

East Asian (EAS) AF: 0.00 AC: 0 AN: 27962

South Asian (SAS) AF: 0.0000488 AC: 3 AN: 61454

European-Finnish (FIN) AF: 0.000999 AC: 28 AN: 28022

Middle Eastern (MID) AF: 0.00226 AC: 5 AN: 2214

European-Non Finnish (NFE) AF: 0.000111 AC: 32 AN: 288140

Other (OTH) AF: 0.00154 AC: 42 AN: 27328

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

African (AFR) AF: 0.0142 AC: 590 AN: 41552

American (AMR) AF: 0.00150 AC: 23 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68024

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00289 Hom.: 2

Bravo AF: 0.00476

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.8
DANN	Benign	0.58
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs45509391; hg19: chr20-61977834;