Variant 1-40784146-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004700.4(KCNQ4):c.53C>G(p.Ala18Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000581 in 1,032,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A18S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000068 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000056 ( 0 hom. )

Consequence

KCNQ4
NM_004700.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.745

Variant links:

Genes affected

KCNQ4 (HGNC:6298): (potassium voltage-gated channel subfamily Q member 4) The protein encoded by this gene forms a potassium channel that is thought to play a critical role in the regulation of neuronal excitability, particularly in sensory cells of the cochlea. The current generated by this channel is inhibited by M1 muscarinic acetylcholine receptors and activated by retigabine, a novel anti-convulsant drug. The encoded protein can form a homomultimeric potassium channel or possibly a heteromultimeric channel in association with the protein encoded by the KCNQ3 gene. Defects in this gene are a cause of nonsyndromic sensorineural deafness type 2 (DFNA2), an autosomal dominant form of progressive hearing loss. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

KCNQ4 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13595283).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ4	NM_004700.4 link	c.53C>G	p.Ala18Gly	missense_variant	Exon 1 of 14	ENST00000347132.10	NP_004691.2	P56696-1B3KQH8
KCNQ4	NM_172163.3 link	c.53C>G	p.Ala18Gly	missense_variant	Exon 1 of 13		NP_751895.1	P56696-2B3KQH8
KCNQ4	XM_047434057.1 link	c.53C>G	p.Ala18Gly	missense_variant	Exon 1 of 13		XP_047290013.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ4	ENST00000347132.10 link	c.53C>G	p.Ala18Gly	missense_variant	Exon 1 of 14	1	NM_004700.4	ENSP00000262916.6		P56696-1
KCNQ4	ENST00000509682.6 link	c.53C>G	p.Ala18Gly	missense_variant	Exon 1 of 13	5		ENSP00000423756.2		P56696-2

Frequencies

GnomAD3 genomes

AF:

0.00000682

AC:

AN:

146666

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000565

AC:

AN:

885416

Hom.:

Cov.:

AF XY:

0.00000940

AC XY:

AN XY:

425636

show subpopulations

Gnomad4 AFR exome

AF:

0.0000604

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000368

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000385

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000682

AC:

AN:

146666

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.20

T;T;.

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.45

.;T;T

M_CAP

Pathogenic

0.96

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Uncertain

0.25

MutationAssessor

Benign

0.0

N;N;N

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.19

.;N;N

REVEL

Benign

0.28

Sift

Benign

0.42

.;T;T

Sift4G

Benign

0.50

.;T;T

Polyphen

0.011

B;B;B

Vest4

0.080, 0.15

MutPred

0.15

Gain of catalytic residue at A18 (P = 0.0435);Gain of catalytic residue at A18 (P = 0.0435);Gain of catalytic residue at A18 (P = 0.0435);

MVP

0.57

MPC

1.1

ClinPred

0.074

GERP RS

1.7

Varity_R

0.060

gMVP

0.37

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over