chr20-63350042-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000744.7(CHRNA4):c.1369G>A(p.Ala457Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A457P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CHRNA4
NM_000744.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.228

Publications

4 publications found

Variant links:

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

CHRNA4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08895522).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CHRNA4	NM_000744.7 link	c.1369G>A	p.Ala457Thr	missense_variant	Exon 5 of 6	ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2 link	c.841G>A	p.Ala281Thr	missense_variant	Exon 5 of 6		NP_001243502.1
CHRNA4	NR_046317.2 link	n.1578G>A		non_coding_transcript_exon_variant	Exon 5 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9 link	c.1369G>A	p.Ala457Thr	missense_variant	Exon 5 of 6	1	NM_000744.7	ENSP00000359285.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1363434

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

667688

African (AFR)

AF:

0.00

AC:

AN:

30970

American (AMR)

AF:

0.00

AC:

AN:

31934

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21534

East Asian (EAS)

AF:

0.00

AC:

AN:

37252

South Asian (SAS)

AF:

0.00

AC:

AN:

71402

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5154

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1063368

Other (OTH)

AF:

0.00

AC:

AN:

56228

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 13, 2016

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The A457T variant in the CHRNA4 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The A457T variant was not observed in approximately 6200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A457T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. We interpret A457T as a variant of uncertain significance. -

Autosomal dominant nocturnal frontal lobe epilepsy 1

Uncertain:1

Nov 04, 2022

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.49

CADD

Benign

7.8

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.27

T;.

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.62

T;T

M_CAP

Benign

0.065

MetaRNN

Benign

0.089

T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.3

L;.

PhyloP100

-0.23

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.050

N;.

REVEL

Benign

0.15

Sift

Benign

0.38

T;.

Sift4G

Benign

0.65

T;T

Polyphen

0.051

B;.

Vest4

0.069

MVP

0.74

MPC

0.40

ClinPred

0.18

GERP RS

1.4

Varity_R

0.046

gMVP

0.28

Mutation Taster

=88/12

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over