chr20-63346486-G-A

Variant names:

• chr20-63346486-G-A
• rs113458361
• ENST00000463705.5:n.2784C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000744.7(CHRNA4):​c.*252C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00194 in 664,088 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (5 hom.)
• Consequence: CHRNA4 NM_000744.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.156
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 20-63346486-G-A is Benign according to our data. Variant chr20-63346486-G-A is described in ClinVar as [Benign]. Clinvar id is 1222092.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 233 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.*252C>T		3_prime_UTR_variant	Exon 6 of 6	ENST00000370263.9	NP_000735.1
CHRNA4	NR_046317.2	n.2345C>T		non_coding_transcript_exon_variant	Exon 6 of 6
CHRNA4	NM_001256573.2	c.*252C>T		3_prime_UTR_variant	Exon 6 of 6		NP_001243502.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9	c.*252C>T		3_prime_UTR_variant	Exon 6 of 6	1	NM_000744.7	ENSP00000359285.4

Frequencies

GnomAD3 genomes AF: 0.00153 AC: 233 AN: 152138 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00223

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00166 AC: 217 AN: 130622 AF XY: 0.00175

Gnomad AFR exome AF: 0.000164

Gnomad AMR exome AF: 0.000862

Gnomad ASJ exome AF: 0.00543

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000742

Gnomad NFE exome AF: 0.00245

Gnomad OTH exome AF: 0.00200

GnomAD4 exome AF: 0.00206 AC: 1054 AN: 511832 Hom.: 5 Cov.: 5 AF XY: 0.00205 AC XY: 570 AN XY: 277818

African (AFR) AF: 0.000201 AC: 3 AN: 14916

American (AMR) AF: 0.000813 AC: 27 AN: 33208

Ashkenazi Jewish (ASJ) AF: 0.00730 AC: 137 AN: 18766

East Asian (EAS) AF: 0.00 AC: 0 AN: 28726

South Asian (SAS) AF: 0.000666 AC: 41 AN: 61550

European-Finnish (FIN) AF: 0.000898 AC: 26 AN: 28962

Middle Eastern (MID) AF: 0.00484 AC: 11 AN: 2272

European-Non Finnish (NFE) AF: 0.00256 AC: 756 AN: 295458

Other (OTH) AF: 0.00189 AC: 53 AN: 27974

GnomAD4 genome AF: 0.00153 AC: 233 AN: 152256 Hom.: 1 Cov.: 33 AF XY: 0.00132 AC XY: 98 AN XY: 74430

African (AFR) AF: 0.000578 AC: 24 AN: 41556

American (AMR) AF: 0.000980 AC: 15 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00224 AC: 152 AN: 68008

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00155 Hom.: 1

Bravo AF: 0.00167

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 28, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.0
DANN	Benign	0.45
PhyloP100		0.16
Mutation Taster		=100/0	polymorphism

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: rs113458361; hg19: chr20-61977838;