rs1044397

Variant names:

• chr20-63349752-C-T
• rs1044397
• NM_000744.7:c.1659G>A

Your query was ambiguous. Multiple possible variants found:

• chr20-63349752-C-T
• chr20-63349752-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000744.7(CHRNA4):​c.1659G>A​(p.Ala553Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.516 in 1,611,664 control chromosomes in the GnomAD database, including 222,578 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (15300 hom., cov: 34)
  • Exomes 𝑓: 0.53 (207278 hom.)
• Consequence: CHRNA4 NM_000744.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -3.63
• Publications: 47 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 20-63349752-C-T is Benign according to our data. Variant chr20-63349752-C-T is described in ClinVar as Benign. ClinVar VariationId is 93428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.63 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.537 is higher than 0.05.

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.1659G>A	p.Ala553Ala	synonymous	Exon 5 of 6	NP_000735.1	P43681-1
	CHRNA4	NM_001256573.2		c.1131G>A	p.Ala377Ala	synonymous	Exon 5 of 6	NP_001243502.1	Q4VAQ3
	CHRNA4	NR_046317.2		n.1868G>A		non_coding_transcript_exon	Exon 5 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA4	ENST00000370263.9	TSL:1 MANE Select	c.1659G>A	p.Ala553Ala	synonymous	Exon 5 of 6	ENSP00000359285.4	P43681-1
	CHRNA4	ENST00000463705.5	TSL:1	n.2307G>A		non_coding_transcript_exon	Exon 4 of 5
	CHRNA4	ENST00000467563.3	TSL:1	n.1729G>A		non_coding_transcript_exon	Exon 5 of 6

Frequencies

GnomAD3 genomes AF: 0.410 AC: 62297 AN: 152040 Hom.: 15290 Cov.: 34

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.378

Gnomad AMR AF: 0.501

Gnomad ASJ AF: 0.432

Gnomad EAS AF: 0.380

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.527

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.417

GnomAD2 exomes AF: 0.482 AC: 119354 AN: 247732 AF XY: 0.485

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.530

Gnomad ASJ exome AF: 0.431

Gnomad EAS exome AF: 0.390

Gnomad FIN exome AF: 0.533

Gnomad NFE exome AF: 0.540

Gnomad OTH exome AF: 0.492

GnomAD4 exome AF: 0.527 AC: 768498 AN: 1459506 Hom.: 207278 Cov.: 72 AF XY: 0.524 AC XY: 380500 AN XY: 725962

African (AFR) AF: 0.109 AC: 3644 AN: 33450

American (AMR) AF: 0.527 AC: 23547 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.424 AC: 11055 AN: 26076

East Asian (EAS) AF: 0.399 AC: 15825 AN: 39664

South Asian (SAS) AF: 0.441 AC: 38025 AN: 86200

European-Finnish (FIN) AF: 0.531 AC: 27719 AN: 52156

Middle Eastern (MID) AF: 0.391 AC: 2252 AN: 5764

European-Non Finnish (NFE) AF: 0.555 AC: 616475 AN: 1111234

Other (OTH) AF: 0.497 AC: 29956 AN: 60318

GnomAD4 genome AF: 0.410 AC: 62316 AN: 152158 Hom.: 15300 Cov.: 34 AF XY: 0.414 AC XY: 30808 AN XY: 74392

African (AFR) AF: 0.129 AC: 5379 AN: 41542

American (AMR) AF: 0.501 AC: 7656 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.432 AC: 1498 AN: 3470

East Asian (EAS) AF: 0.380 AC: 1959 AN: 5152

South Asian (SAS) AF: 0.429 AC: 2069 AN: 4818

European-Finnish (FIN) AF: 0.527 AC: 5591 AN: 10600

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.542 AC: 36820 AN: 67978

Other (OTH) AF: 0.422 AC: 888 AN: 2106

Alfa AF: 0.492 Hom.: 12797

Bravo AF: 0.394

Asia WGS AF: 0.393 AC: 1370 AN: 3478

EpiCase AF: 0.527

EpiControl AF: 0.520

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Autosomal dominant nocturnal frontal lobe epilepsy (1)
-	-	1	Autosomal dominant nocturnal frontal lobe epilepsy 1 (1)
-	-	1	Inborn genetic diseases (1)
-	-	-	NICOTINE ADDICTION, PROTECTION AGAINST (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.057
DANN	Benign	0.58
PhyloP100		-3.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs1044397; hg19: chr20-61981104; COSMIC: COSV64719459; COSMIC: COSV64719459;