20-63359522-T-C

Variant names:

• chr20-63359522-T-C
• rs6090384
• NM_000744.7:c.228+26A>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.228+26A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.942 in 1,612,210 control chromosomes in the GnomAD database, including 718,042 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (59636 hom., cov: 33)
  • Exomes 𝑓: 0.95 (658406 hom.)
• Consequence: CHRNA4 NM_000744.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.435
• Publications: 15 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=-0.95).
• BP6: Variant 20-63359522-T-C is Benign according to our data. Variant chr20-63359522-T-C is described in ClinVar as Benign. ClinVar VariationId is 670759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.228+26A>G		intron_variant	Intron 2 of 5	ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2	c.-319+26A>G		intron_variant	Intron 2 of 5		NP_001243502.1
CHRNA4	NR_046317.2	n.412+26A>G		intron_variant	Intron 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9	c.228+26A>G		intron_variant	Intron 2 of 5	1	NM_000744.7	ENSP00000359285.4

Frequencies

GnomAD3 genomes AF: 0.876 AC: 133184 AN: 152098 Hom.: 59606 Cov.: 33

Gnomad AFR AF: 0.666

Gnomad AMI AF: 0.996

Gnomad AMR AF: 0.938

Gnomad ASJ AF: 0.925

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.955

Gnomad FIN AF: 0.980

Gnomad MID AF: 0.946

Gnomad NFE AF: 0.953

Gnomad OTH AF: 0.891

GnomAD2 exomes AF: 0.939 AC: 234117 AN: 249274 AF XY: 0.943

Gnomad AFR exome AF: 0.654

Gnomad AMR exome AF: 0.965

Gnomad ASJ exome AF: 0.923

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.977

Gnomad NFE exome AF: 0.953

Gnomad OTH exome AF: 0.943

GnomAD4 exome AF: 0.948 AC: 1384755 AN: 1459994 Hom.: 658406 Cov.: 49 AF XY: 0.949 AC XY: 689538 AN XY: 726300

African (AFR) AF: 0.655 AC: 21922 AN: 33472

American (AMR) AF: 0.962 AC: 43017 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.925 AC: 24164 AN: 26122

East Asian (EAS) AF: 1.00 AC: 39685 AN: 39696

South Asian (SAS) AF: 0.951 AC: 82037 AN: 86240

European-Finnish (FIN) AF: 0.975 AC: 50626 AN: 51932

Middle Eastern (MID) AF: 0.930 AC: 5351 AN: 5756

European-Non Finnish (NFE) AF: 0.955 AC: 1061393 AN: 1111732

Other (OTH) AF: 0.938 AC: 56560 AN: 60330

GnomAD4 genome AF: 0.876 AC: 133268 AN: 152216 Hom.: 59636 Cov.: 33 AF XY: 0.882 AC XY: 65593 AN XY: 74410

African (AFR) AF: 0.666 AC: 27626 AN: 41484

American (AMR) AF: 0.939 AC: 14370 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.925 AC: 3210 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5169 AN: 5172

South Asian (SAS) AF: 0.956 AC: 4607 AN: 4820

European-Finnish (FIN) AF: 0.980 AC: 10390 AN: 10606

Middle Eastern (MID) AF: 0.952 AC: 280 AN: 294

European-Non Finnish (NFE) AF: 0.953 AC: 64824 AN: 68034

Other (OTH) AF: 0.892 AC: 1884 AN: 2112

Alfa AF: 0.934 Hom.: 89228

Bravo AF: 0.862

Asia WGS AF: 0.964 AC: 3351 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

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 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Autosomal dominant nocturnal frontal lobe epilepsy 1 Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

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 100% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 93. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.30
DANN	Benign	0.36
PhyloP100		-0.43
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: rs6090384; hg19: chr20-61990874;