chr20-63356425-C-T

Variant names:

• chr20-63356425-C-T
• rs776781462
• NM_000744.7:c.229-10G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PM2 PP3_Moderate BP6 BS2

The NM_000744.7(CHRNA4):​c.229-10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000345 in 1,447,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: CHRNA4 NM_000744.7 intron
• Scores: Splicing: ADA: 0.5870
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.428
• 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_ADA.
• BP6: Variant 20-63356425-C-T is Benign according to our data. Variant chr20-63356425-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 582974.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.229-10G>A		intron_variant	Intron 2 of 5	ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2	c.-318-10G>A		intron_variant	Intron 2 of 5		NP_001243502.1
CHRNA4	NR_046317.2	n.413-10G>A		intron_variant	Intron 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9	c.229-10G>A		intron_variant	Intron 2 of 5	1	NM_000744.7	ENSP00000359285.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000134 AC: 3 AN: 223806 AF XY: 0.00000829

Gnomad AFR exome AF: 0.0000729

Gnomad AMR exome AF: 0.0000308

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000101

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1447368 Hom.: 0 Cov.: 32 AF XY: 0.00000418 AC XY: 3 AN XY: 718354

African (AFR) AF: 0.0000301 AC: 1 AN: 33266

American (AMR) AF: 0.0000231 AC: 1 AN: 43296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25756

East Asian (EAS) AF: 0.00 AC: 0 AN: 39198

South Asian (SAS) AF: 0.00 AC: 0 AN: 83558

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1105446

Other (OTH) AF: 0.00 AC: 0 AN: 59810

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Dec 27, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; Located in a region that tolerates variation and lacks pathogenic variants; Has not been previously published as pathogenic or benign to our knowledge -

not specified Benign:1

Aug 30, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant nocturnal frontal lobe epilepsy Benign:1

Aug 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely 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	-0.84
CADD	Benign	22
DANN	Benign	0.46
PhyloP100		-0.43

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.59
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: -2
DS_AL_spliceai		0.59		Position offset: -10

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs776781462; hg19: chr20-61987777;