1-40824182-G-A

Position:

chr1-40824182-G-A

Variant summary

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

The NM_004700.4(KCNQ4):c.1216G>A(p.Asp406Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000493 in 1,420,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

KCNQ4
NM_004700.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.51

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:

KCNQ4 (HGNC:):

KCNQ4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17281964).

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ4	NM_004700.4 linkuse as main transcript	c.1216G>A	p.Asp406Asn	missense_variant	9/14	ENST00000347132.10	NP_004691.2	P56696-1B3KQH8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KCNQ4	ENST00000347132.10 linkuse as main transcript	c.1216G>A	p.Asp406Asn	missense_variant	9/14	1	NM_004700.4	ENSP00000262916.6	P56696-1
KCNQ4	ENST00000509682.6 linkuse as main transcript	c.1130+1780G>A		intron_variant		5		ENSP00000423756.2	P56696-2
KCNQ4	ENST00000443478.3 linkuse as main transcript	c.815+1780G>A		intron_variant		5		ENSP00000406735.3	H0Y6N7
KCNQ4	ENST00000506017.1 linkuse as main transcript	n.535G>A		non_coding_transcript_exon_variant	6/11	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000568

AC:

AN:

176042

Hom.:

AF XY:

0.0000104

AC XY:

AN XY:

96372

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000616

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000493

AC:

AN:

1420228

Hom.:

Cov.:

AF XY:

0.00000853

AC XY:

AN XY:

703076

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000253

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000205

Gnomad4 NFE exome

AF:

0.00000458

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 10, 2017

The p.Asp406Asn variant in KCNQ4 has not been previously reported in individuals with hearing loss, but has been identified in 1/68584 European chromosomes and in 1/16162 Finnish chromosomes and 1/68584 non-Finnish European chromosomes by t he Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Altho ugh this variant has been seen in the general population, its frequency is not h igh enough to rule out a pathogenic role. Computational prediction tools and con servation analysis suggest that the p.Asp406Asn variant may not impact the prote in, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Asp406Asn variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.047

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;T

Eigen

Benign

-0.11

Eigen_PC

Benign

0.059

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.79

.;T

M_CAP

Benign

0.052

MetaRNN

Benign

0.17

T;T

MetaSVM

Uncertain

0.79

MutationAssessor

Benign

0.34

N;N

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.4

.;N

REVEL

Uncertain

0.35

Sift

Benign

0.13

.;T

Sift4G

Benign

0.23

.;T

Polyphen

0.33

B;B

Vest4

0.37

MutPred

0.11

Gain of glycosylation at P409 (P = 0.1689);Gain of glycosylation at P409 (P = 0.1689);

MVP

0.72

MPC

0.14

ClinPred

0.33

GERP RS

4.6

Varity_R

0.13

gMVP

0.41

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over