1-40837737-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004700.4(KCNQ4):c.1818C>G(p.Asp606Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000788 in 1,612,604 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0013 ( 5 hom., cov: 31)

Exomes 𝑓: 0.00074 ( 19 hom. )

Consequence

KCNQ4
NM_004700.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.164

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

autosomal dominant nonsyndromic hearing loss 2A
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
nonsyndromic genetic hearing loss
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hearing loss disorder
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

KCNQ4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022726655).

BP6

Variant 1-40837737-C-G is Benign according to our data. Variant chr1-40837737-C-G is described in ClinVar as Benign. ClinVar VariationId is 163756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00128 (195/152202) while in subpopulation EAS AF = 0.0349 (180/5160). AF 95% confidence interval is 0.0307. There are 5 homozygotes in GnomAd4. There are 108 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ4	NM_004700.4 link	c.1818C>G	p.Asp606Glu	missense_variant	Exon 13 of 14	ENST00000347132.10	NP_004691.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
KCNQ4	ENST00000347132.10 link	c.1818C>G	p.Asp606Glu	missense_variant	Exon 13 of 14	1	NM_004700.4	ENSP00000262916.6
KCNQ4	ENST00000509682.6 link	c.1656C>G	p.Asp552Glu	missense_variant	Exon 12 of 13	5		ENSP00000423756.2
KCNQ4	ENST00000443478.3 link	c.1398C>G	p.Asp466Glu	missense_variant	Exon 12 of 13	5		ENSP00000406735.3
KCNQ4	ENST00000506017.1 link	n.1137C>G		non_coding_transcript_exon_variant	Exon 10 of 11	2

Frequencies

GnomAD3 genomes

AF:

0.00128

AC:

195

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0348

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00273

AC:

673

AN:

246092

AF XY:

0.00256

show subpopulations

Gnomad AFR exome

AF:

0.000192

Gnomad AMR exome

AF:

0.000176

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0356

Gnomad FIN exome

AF:

0.0000481

Gnomad NFE exome

AF:

0.00000899

Gnomad OTH exome

AF:

0.00100

GnomAD4 exome

AF:

0.000736

AC:

1075

AN:

1460402

Hom.:

Cov.:

AF XY:

0.000686

AC XY:

498

AN XY:

726384

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33470

American (AMR)

AF:

0.000112

AC:

AN:

44522

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26092

East Asian (EAS)

AF:

0.0228

AC:

903

AN:

39676

South Asian (SAS)

AF:

0.000209

AC:

AN:

85920

European-Finnish (FIN)

AF:

0.0000751

AC:

AN:

53236

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111446

Other (OTH)

AF:

0.00226

AC:

136

AN:

60288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

111

167

222

278

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00128

AC:

195

AN:

152202

Hom.:

Cov.:

AF XY:

0.00145

AC XY:

108

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41530

American (AMR)

AF:

0.000196

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0349

AC:

180

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68004

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000897

Hom.:

Bravo

AF:

0.00127

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00256

AC:

311

Asia WGS

AF:

0.00808

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 17033161) -

not specified

Benign:1

Nov 05, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Asp606Glu in exon 13 of KCNQ4: This variant is not expected to have clinical sig nificance because it has been identified in 3.9% (293/7602) of East Asian chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org, dbSNP rs139835231). In addition, it is not conserved across species, including mammals. Of note, kangaroo rat and platypus have glutamate (Glu) at this positi on despite high nearby amino acid conservation. -

Autosomal dominant nonsyndromic hearing loss 2A

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.30

CADD

Benign

2.7

(source)

DANN

Benign

0.37

DEOGEN2

Uncertain

0.51

D;D;.

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.56

.;T;T

MetaRNN

Benign

0.0023

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.36

N;N;.

PhyloP100

0.16

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.040

.;N;N

REVEL

Benign

0.28

Sift

Benign

1.0

.;T;T

Sift4G

Benign

0.86

.;T;T

Polyphen

0.036

B;B;B

Vest4

0.16, 0.17

MutPred

0.41

Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);.;

MVP

0.55

MPC

0.92

ClinPred

0.012

GERP RS

-2.7

Varity_R

0.047

gMVP

0.13

Mutation Taster

=100/0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over