1-40835010-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 1P and 17B. PP3BP6_Very_StrongBP7BA1

The NM_004700.4(KCNQ4):c.1657C>T(p.Leu553Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0479 in 1,614,046 control chromosomes in the GnomAD database, including 2,132 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 102 hom., cov: 31)

Exomes 𝑓: 0.049 ( 2030 hom. )

Consequence

KCNQ4
NM_004700.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.06

Publications

5 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 -16 ACMG points.

PP3

REVEL computational evidence supports a deleterious effect, 0.671

BP6

Variant 1-40835010-C-T is Benign according to our data. Variant chr1-40835010-C-T is described in ClinVar as Benign. ClinVar VariationId is 45102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.06 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0505 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ4	NM_004700.4 link	c.1657C>T	p.Leu553Leu	synonymous_variant	Exon 12 of 14	ENST00000347132.10	NP_004691.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
KCNQ4	ENST00000347132.10 link	c.1657C>T	p.Leu553Leu	synonymous_variant	Exon 12 of 14	1	NM_004700.4	ENSP00000262916.6
KCNQ4	ENST00000509682.6 link	c.1495C>T	p.Leu499Leu	synonymous_variant	Exon 11 of 13	5		ENSP00000423756.2
KCNQ4	ENST00000443478.3 link	c.1237C>T	p.Leu413Leu	synonymous_variant	Exon 11 of 13	5		ENSP00000406735.3
KCNQ4	ENST00000506017.1 link	n.976C>T		non_coding_transcript_exon_variant	Exon 9 of 11	2

Frequencies

GnomAD3 genomes

AF:

0.0329

AC:

5004

AN:

152234

Hom.:

102

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00955

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.0298

Gnomad ASJ

AF:

0.0204

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0520

Gnomad FIN

AF:

0.0156

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0520

Gnomad OTH

AF:

0.0354

GnomAD2 exomes

AF:

0.0351

AC:

8823

AN:

251452

AF XY:

0.0376

show subpopulations

Gnomad AFR exome

AF:

0.00867

Gnomad AMR exome

AF:

0.0203

Gnomad ASJ exome

AF:

0.0211

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.0196

Gnomad NFE exome

AF:

0.0480

Gnomad OTH exome

AF:

0.0399

GnomAD4 exome

AF:

0.0495

AC:

72314

AN:

1461694

Hom.:

2030

Cov.:

AF XY:

0.0501

AC XY:

36411

AN XY:

727148

show subpopulations

African (AFR)

AF:

0.00720

AC:

241

AN:

33480

American (AMR)

AF:

0.0216

AC:

967

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0201

AC:

526

AN:

26136

East Asian (EAS)

AF:

0.000151

AC:

AN:

39694

South Asian (SAS)

AF:

0.0532

AC:

4585

AN:

86256

European-Finnish (FIN)

AF:

0.0220

AC:

1172

AN:

53382

Middle Eastern (MID)

AF:

0.0430

AC:

248

AN:

5766

European-Non Finnish (NFE)

AF:

0.0557

AC:

61982

AN:

1111874

Other (OTH)

AF:

0.0428

AC:

2587

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

3904

7809

11713

15618

19522

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2324

4648

6972

9296

11620

<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:

0.0328

AC:

5000

AN:

152352

Hom.:

102

Cov.:

AF XY:

0.0306

AC XY:

2283

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00950

AC:

395

AN:

41598

American (AMR)

AF:

0.0297

AC:

455

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0204

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.0520

AC:

251

AN:

4826

European-Finnish (FIN)

AF:

0.0156

AC:

166

AN:

10620

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0520

AC:

3535

AN:

68022

Other (OTH)

AF:

0.0350

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

240

480

721

961

1201

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.0442

Hom.:

167

Bravo

AF:

0.0321

Asia WGS

AF:

0.0230

AC:

AN:

3478

EpiCase

AF:

0.0532

EpiControl

AF:

0.0490

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jun 01, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Leu553Leu in Exon 12 of KCNQ4: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 5.0% (350/7020) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs55925184). -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 05, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Autosomal dominant nonsyndromic hearing loss 2A

Benign:1

May 18, 2021

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

BayesDel_noAF

Benign

-0.20

CADD

Benign

6.7

(source)

DANN

Benign

0.72

PhyloP100

1.1

Mutation Taster

=42/58

polymorphism (auto)

(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