rs13374844

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004700.4(KCNQ4):c.315-18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,607,752 control chromosomes in the GnomAD database, including 17,742 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 1967 hom., cov: 33)

Exomes 𝑓: 0.14 ( 15775 hom. )

Consequence

KCNQ4
NM_004700.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.488

Publications

10 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 (BayesDel_noAF=-0.88).

BP6

Variant 1-40817247-C-T is Benign according to our data. Variant chr1-40817247-C-T is described in ClinVar as Benign. ClinVar VariationId is 259521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ4	NM_004700.4 link	c.315-18C>T		intron_variant	Intron 1 of 13	ENST00000347132.10	NP_004691.2	P56696-1B3KQH8

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNQ4	ENST00000347132.10 link	c.315-18C>T	intron_variant	Intron 1 of 13	1	NM_004700.4	ENSP00000262916.6	P56696-1
KCNQ4	ENST00000509682.6 link	c.315-18C>T	intron_variant	Intron 1 of 12	5		ENSP00000423756.2	P56696-2
KCNQ4	ENST00000443478.3 link	c.-19C>T	upstream_gene_variant		5		ENSP00000406735.3	H0Y6N7

Frequencies

GnomAD3 genomes

AF:

0.157

AC:

23918

AN:

152150

Hom.:

1960

Cov.:

show subpopulations

Gnomad AFR

AF:

0.175

Gnomad AMI

AF:

0.200

Gnomad AMR

AF:

0.144

Gnomad ASJ

AF:

0.142

Gnomad EAS

AF:

0.296

Gnomad SAS

AF:

0.170

Gnomad FIN

AF:

0.141

Gnomad MID

AF:

0.161

Gnomad NFE

AF:

0.140

Gnomad OTH

AF:

0.181

GnomAD2 exomes

AF:

0.158

AC:

38702

AN:

245484

AF XY:

0.157

show subpopulations

Gnomad AFR exome

AF:

0.174

Gnomad AMR exome

AF:

0.119

Gnomad ASJ exome

AF:

0.138

Gnomad EAS exome

AF:

0.310

Gnomad FIN exome

AF:

0.143

Gnomad NFE exome

AF:

0.142

Gnomad OTH exome

AF:

0.157

GnomAD4 exome

AF:

0.144

AC:

209839

AN:

1455484

Hom.:

15775

Cov.:

AF XY:

0.144

AC XY:

104464

AN XY:

723898

show subpopulations

African (AFR)

AF:

0.176

AC:

5862

AN:

33366

American (AMR)

AF:

0.121

AC:

5363

AN:

44500

Ashkenazi Jewish (ASJ)

AF:

0.142

AC:

3687

AN:

26032

East Asian (EAS)

AF:

0.275

AC:

10914

AN:

39630

South Asian (SAS)

AF:

0.172

AC:

14752

AN:

85598

European-Finnish (FIN)

AF:

0.144

AC:

7683

AN:

53214

Middle Eastern (MID)

AF:

0.171

AC:

985

AN:

5758

European-Non Finnish (NFE)

AF:

0.137

AC:

151358

AN:

1107284

Other (OTH)

AF:

0.154

AC:

9235

AN:

60102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

8307

16614

24922

33229

41536

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5516

11032

16548

22064

27580

<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:

0.157

AC:

23941

AN:

152268

Hom.:

1967

Cov.:

AF XY:

0.159

AC XY:

11820

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.175

AC:

7267

AN:

41538

American (AMR)

AF:

0.144

AC:

2197

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.142

AC:

493

AN:

3472

East Asian (EAS)

AF:

0.295

AC:

1524

AN:

5172

South Asian (SAS)

AF:

0.170

AC:

823

AN:

4828

European-Finnish (FIN)

AF:

0.141

AC:

1493

AN:

10608

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.140

AC:

9522

AN:

68028

Other (OTH)

AF:

0.188

AC:

398

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1081

2162

3242

4323

5404

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

256

512

768

1024

1280

<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:

0.153

Hom.:

774

Bravo

AF:

0.159

Asia WGS

AF:

0.238

AC:

825

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 29, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

BayesDel_noAF

Benign

-0.88

CADD

Benign

1.3

(source)

DANN

Benign

0.28

PhyloP100

-0.49

PromoterAI

-0.0094

Neutral

(source)

Mutation Taster

=32/68

disease causing

(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