1-40784233-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 8P and 6B. PP5_Very_StrongBP4BS1_SupportingBS2

The NM_004700.4(KCNQ4):c.140T>C(p.Leu47Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,297,126 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

KCNQ4
NM_004700.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 2.11

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP5

Variant 1-40784233-T-C is Pathogenic according to our data. Variant chr1-40784233-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 585006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.37299556). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000027 (31/1148478) while in subpopulation EAS AF= 0.00132 (31/23568). AF 95% confidence interval is 0.000952. There are 0 homozygotes in gnomad4_exome. There are 16 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ4	NM_004700.4 link	c.140T>C	p.Leu47Pro	missense_variant	Exon 1 of 14	ENST00000347132.10	NP_004691.2	P56696-1B3KQH8
KCNQ4	NM_172163.3 link	c.140T>C	p.Leu47Pro	missense_variant	Exon 1 of 13		NP_751895.1	P56696-2B3KQH8
KCNQ4	XM_047434057.1 link	c.140T>C	p.Leu47Pro	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.140T>C	p.Leu47Pro	missense_variant	Exon 1 of 14	1	NM_004700.4	ENSP00000262916.6		P56696-1
KCNQ4	ENST00000509682.6 link	c.140T>C	p.Leu47Pro	missense_variant	Exon 1 of 13	5		ENSP00000423756.2		P56696-2

Frequencies

GnomAD3 genomes

AF:

0.0000135

AC:

AN:

148648

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:

0.000401

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000270

AC:

AN:

1148478

Hom.:

Cov.:

AF XY:

0.0000286

AC XY:

AN XY:

559294

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00132

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000135

AC:

AN:

148648

Hom.:

Cov.:

AF XY:

0.0000276

AC XY:

AN XY:

72456

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000401

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 2A

Pathogenic:2

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 20, 2017

Laboratory of Molecular Genetics, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

In family YUHL48, individual YUHL48-11 had moderate bilateral sensorineural hearing loss at the age of 18 years, which progressed to profound hearing loss by the age of 41 years. -

not provided

Pathogenic:1

Jun 21, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect; variant reduces voltage-gated potassium channel activity in a dominant negative mechanism (PMID: 30556268); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34712263, 36147510, 31434872, 37009795, 36597364, 34519870, 34515852, 36140355, 30556268) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Benign

0.90

DEOGEN2

Uncertain

0.61

D;D;.

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.38

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.57

.;T;T

M_CAP

Pathogenic

0.96

MetaRNN

Benign

0.37

T;T;T

MetaSVM

Uncertain

0.79

MutationAssessor

Uncertain

2.3

M;M;M

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-2.3

.;N;D

REVEL

Uncertain

0.36

Sift

Benign

0.095

.;T;T

Sift4G

Uncertain

0.0030

.;D;D

Polyphen

0.017

B;B;B

Vest4

0.35, 0.43

MutPred

0.24

Loss of stability (P = 0.0178);Loss of stability (P = 0.0178);Loss of stability (P = 0.0178);

MVP

0.75

MPC

2.2

ClinPred

0.22

GERP RS

1.9

Varity_R

0.49

gMVP

0.71

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