rs2273506

Variant names:

• chr20-63359587-G-A
• rs2273506
• NM_000744.7:c.189C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001256573.2(CHRNA4):​c.-358C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0793 in 1,612,634 control chromosomes in the GnomAD database, including 5,925 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.096 (747 hom., cov: 34)
  • Exomes 𝑓: 0.078 (5178 hom.)
• Consequence: CHRNA4 NM_001256573.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -3.33
• Publications: 18 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 20-63359587-G-A is Benign according to our data. Variant chr20-63359587-G-A is described in ClinVar as Benign. ClinVar VariationId is 128747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256573.2. 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.189C>T	p.Leu63Leu	synonymous	Exon 2 of 6	NP_000735.1	P43681-1
	CHRNA4	NM_001256573.2		c.-358C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 6	NP_001243502.1	Q4VAQ3
	CHRNA4	NM_001256573.2		c.-358C>T		5_prime_UTR	Exon 2 of 6	NP_001243502.1	Q4VAQ3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA4	ENST00000370263.9	TSL:1 MANE Select	c.189C>T	p.Leu63Leu	synonymous	Exon 2 of 6	ENSP00000359285.4	P43681-1
	CHRNA4	ENST00000467563.3	TSL:1	n.241C>T		non_coding_transcript_exon	Exon 2 of 6
	CHRNA4	ENST00000627000.1	TSL:1	n.189C>T		non_coding_transcript_exon	Exon 2 of 6	ENSP00000486914.1	A0A0D9SFU6

Frequencies

GnomAD3 genomes AF: 0.0957 AC: 14561 AN: 152168 Hom.: 745 Cov.: 34

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.0764

Gnomad ASJ AF: 0.0884

Gnomad EAS AF: 0.127

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.0873

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.0712

Gnomad OTH AF: 0.105

GnomAD2 exomes AF: 0.0924 AC: 23078 AN: 249840 AF XY: 0.0953

Gnomad AFR exome AF: 0.134

Gnomad AMR exome AF: 0.0478

Gnomad ASJ exome AF: 0.0963

Gnomad EAS exome AF: 0.130

Gnomad FIN exome AF: 0.0886

Gnomad NFE exome AF: 0.0746

Gnomad OTH exome AF: 0.0913

GnomAD4 exome AF: 0.0776 AC: 113252 AN: 1460348 Hom.: 5178 Cov.: 38 AF XY: 0.0799 AC XY: 58052 AN XY: 726460

African (AFR) AF: 0.142 AC: 4739 AN: 33476

American (AMR) AF: 0.0510 AC: 2281 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 2638 AN: 26128

East Asian (EAS) AF: 0.122 AC: 4856 AN: 39694

South Asian (SAS) AF: 0.160 AC: 13826 AN: 86258

European-Finnish (FIN) AF: 0.0869 AC: 4525 AN: 52082

Middle Eastern (MID) AF: 0.167 AC: 959 AN: 5756

European-Non Finnish (NFE) AF: 0.0668 AC: 74321 AN: 1111878

Other (OTH) AF: 0.0846 AC: 5107 AN: 60358

GnomAD4 genome AF: 0.0958 AC: 14584 AN: 152286 Hom.: 747 Cov.: 34 AF XY: 0.0967 AC XY: 7199 AN XY: 74460

African (AFR) AF: 0.133 AC: 5535 AN: 41540

American (AMR) AF: 0.0764 AC: 1170 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0884 AC: 307 AN: 3472

East Asian (EAS) AF: 0.128 AC: 664 AN: 5190

South Asian (SAS) AF: 0.163 AC: 787 AN: 4822

European-Finnish (FIN) AF: 0.0873 AC: 927 AN: 10616

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.0712 AC: 4846 AN: 68024

Other (OTH) AF: 0.103 AC: 217 AN: 2108

Alfa AF: 0.0848 Hom.: 1007

Bravo AF: 0.0942

Asia WGS AF: 0.145 AC: 502 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Autosomal dominant nocturnal frontal lobe epilepsy 1 (4)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Autosomal dominant nocturnal frontal lobe epilepsy (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.13
DANN	Benign	0.93
PhyloP100		-3.3
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: rs2273506; hg19: chr20-61990939; COSMIC: COSV64717572; COSMIC: COSV64717572;