rs2273502

Variant names:

• chr20-63356470-C-T
• rs2273502
• NM_000744.7:c.229-55G>A

Variant summary

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

The NM_000744.7(CHRNA4):​c.229-55G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0799 in 1,528,598 control chromosomes in the GnomAD database, including 5,730 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.096 (753 hom., cov: 31)
  • Exomes 𝑓: 0.078 (4977 hom.)
• Consequence: CHRNA4 NM_000744.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.892
• Publications: 12 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: Labcorp Genetics (formerly Invitae), G2P
• 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=-0.89).
• BP6: Variant 20-63356470-C-T is Benign according to our data. Variant chr20-63356470-C-T is described in ClinVar as Benign. ClinVar VariationId is 1238055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.229-55G>A		intron_variant	Intron 2 of 5	ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2	c.-318-55G>A		intron_variant	Intron 2 of 5		NP_001243502.1
CHRNA4	NR_046317.2	n.413-55G>A		intron_variant	Intron 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9	c.229-55G>A		intron_variant	Intron 2 of 5	1	NM_000744.7	ENSP00000359285.4

Frequencies

GnomAD3 genomes AF: 0.0962 AC: 14600 AN: 151792 Hom.: 751 Cov.: 31

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.0813

Gnomad AMR AF: 0.0766

Gnomad ASJ AF: 0.0885

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.0873

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.0713

Gnomad OTH AF: 0.105

GnomAD4 exome AF: 0.0781 AC: 107574 AN: 1376688 Hom.: 4977 Cov.: 24 AF XY: 0.0805 AC XY: 54932 AN XY: 682258

African (AFR) AF: 0.145 AC: 4551 AN: 31434

American (AMR) AF: 0.0543 AC: 2012 AN: 37022

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 2566 AN: 25078

East Asian (EAS) AF: 0.124 AC: 4558 AN: 36710

South Asian (SAS) AF: 0.162 AC: 12890 AN: 79380

European-Finnish (FIN) AF: 0.0877 AC: 4252 AN: 48468

Middle Eastern (MID) AF: 0.168 AC: 953 AN: 5660

European-Non Finnish (NFE) AF: 0.0671 AC: 70873 AN: 1055662

Other (OTH) AF: 0.0859 AC: 4919 AN: 57274

GnomAD4 genome AF: 0.0963 AC: 14625 AN: 151910 Hom.: 753 Cov.: 31 AF XY: 0.0972 AC XY: 7220 AN XY: 74258

African (AFR) AF: 0.134 AC: 5569 AN: 41406

American (AMR) AF: 0.0766 AC: 1171 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0885 AC: 307 AN: 3468

East Asian (EAS) AF: 0.130 AC: 670 AN: 5144

South Asian (SAS) AF: 0.164 AC: 789 AN: 4800

European-Finnish (FIN) AF: 0.0873 AC: 925 AN: 10592

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

European-Non Finnish (NFE) AF: 0.0713 AC: 4845 AN: 67910

Other (OTH) AF: 0.104 AC: 218 AN: 2104

Alfa AF: 0.0824 Hom.: 368

Bravo AF: 0.0949

Asia WGS AF: 0.148 AC: 512 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	12
DANN	Benign	0.65
PhyloP100		0.89
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2273502; hg19: chr20-61987822; COSMIC: COSV64718293; COSMIC: COSV64718293;