rs3827020

Variant names:

• chr20-63349639-T-C
• rs3827020
• NM_000744.7:c.1758+14A>G

Your query was ambiguous. Multiple possible variants found:

• chr20-63349639-T-C
• chr20-63349639-T-G

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.1758+14A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 1,612,344 control chromosomes in the GnomAD database, including 32,367 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3203 hom., cov: 34)
  • Exomes 𝑓: 0.19 (29164 hom.)
• Consequence: CHRNA4 NM_000744.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -7.11
• Publications: 13 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=-0.93).
• BP6: Variant 20-63349639-T-C is Benign according to our data. Variant chr20-63349639-T-C is described in ClinVar as Benign. ClinVar VariationId is 93429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.1758+14A>G		intron_variant	Intron 5 of 5	ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2	c.1230+14A>G		intron_variant	Intron 5 of 5		NP_001243502.1
CHRNA4	NR_046317.2	n.1967+14A>G		intron_variant	Intron 5 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9	c.1758+14A>G		intron_variant	Intron 5 of 5	1	NM_000744.7	ENSP00000359285.4

Frequencies

GnomAD3 genomes AF: 0.197 AC: 29983 AN: 152102 Hom.: 3202 Cov.: 34

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.297

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.208

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.186

Gnomad OTH AF: 0.198

GnomAD2 exomes AF: 0.217 AC: 53721 AN: 247432 AF XY: 0.210

Gnomad AFR exome AF: 0.170

Gnomad AMR exome AF: 0.299

Gnomad ASJ exome AF: 0.147

Gnomad EAS exome AF: 0.467

Gnomad FIN exome AF: 0.199

Gnomad NFE exome AF: 0.183

Gnomad OTH exome AF: 0.194

GnomAD4 exome AF: 0.192 AC: 280902 AN: 1460124 Hom.: 29164 Cov.: 32 AF XY: 0.192 AC XY: 139178 AN XY: 726396

African (AFR) AF: 0.174 AC: 5809 AN: 33466

American (AMR) AF: 0.289 AC: 12914 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 4037 AN: 26122

East Asian (EAS) AF: 0.463 AC: 18378 AN: 39688

South Asian (SAS) AF: 0.163 AC: 14045 AN: 86254

European-Finnish (FIN) AF: 0.200 AC: 10409 AN: 51998

Middle Eastern (MID) AF: 0.153 AC: 880 AN: 5766

European-Non Finnish (NFE) AF: 0.182 AC: 202702 AN: 1111748

Other (OTH) AF: 0.194 AC: 11728 AN: 60362

GnomAD4 genome AF: 0.197 AC: 29990 AN: 152220 Hom.: 3203 Cov.: 34 AF XY: 0.198 AC XY: 14734 AN XY: 74426

African (AFR) AF: 0.176 AC: 7308 AN: 41542

American (AMR) AF: 0.220 AC: 3364 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 515 AN: 3472

East Asian (EAS) AF: 0.474 AC: 2449 AN: 5168

South Asian (SAS) AF: 0.164 AC: 791 AN: 4826

European-Finnish (FIN) AF: 0.208 AC: 2203 AN: 10608

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.186 AC: 12626 AN: 67982

Other (OTH) AF: 0.200 AC: 422 AN: 2114

Alfa AF: 0.137 Hom.: 357

Bravo AF: 0.201

Asia WGS AF: 0.319 AC: 1107 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant nocturnal frontal lobe epilepsy 1 Benign:3

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 14, 2016

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 38% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 35. Only high quality variants are reported. -

Jun 07, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autosomal dominant nocturnal frontal lobe epilepsy Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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	-0.93
CADD	Benign	0.052
DANN	Benign	0.26
PhyloP100		-7.1
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: rs3827020; hg19: chr20-61980991; COSMIC: COSV64720175; COSMIC: COSV64720175;