1-40817249-C-T

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.315-16C>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 1,608,150 control chromosomes in the GnomAD database, including 17,653 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 1925 hom., cov: 32)

Exomes 𝑓: 0.14 ( 15728 hom. )

Consequence

KCNQ4
NM_004700.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.288

Publications

9 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=-0.83).

BP6

Variant 1-40817249-C-T is Benign according to our data. Variant chr1-40817249-C-T is described in ClinVar as Benign. ClinVar VariationId is 259519.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.315-16C>T		intron_variant	Intron 1 of 13	ENST00000347132.10	NP_004691.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
KCNQ4	ENST00000347132.10 link	c.315-16C>T	intron_variant	Intron 1 of 13	1	NM_004700.4	ENSP00000262916.6
KCNQ4	ENST00000509682.6 link	c.315-16C>T	intron_variant	Intron 1 of 12	5		ENSP00000423756.2
KCNQ4	ENST00000443478.3 link	c.-17C>T	upstream_gene_variant		5		ENSP00000406735.3

Frequencies

GnomAD3 genomes

AF:

0.156

AC:

23666

AN:

152146

Hom.:

1919

Cov.:

show subpopulations

Gnomad AFR

AF:

0.169

Gnomad AMI

AF:

0.200

Gnomad AMR

AF:

0.143

Gnomad ASJ

AF:

0.142

Gnomad EAS

AF:

0.295

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:

0.157

AC:

38664

AN:

246148

AF XY:

0.157

show subpopulations

Gnomad AFR exome

AF:

0.167

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:

209651

AN:

1455886

Hom.:

15728

Cov.:

AF XY:

0.144

AC XY:

104377

AN XY:

724158

show subpopulations

African (AFR)

AF:

0.169

AC:

5652

AN:

33378

American (AMR)

AF:

0.120

AC:

5351

AN:

44520

Ashkenazi Jewish (ASJ)

AF:

0.142

AC:

3688

AN:

26042

East Asian (EAS)

AF:

0.275

AC:

10914

AN:

39634

South Asian (SAS)

AF:

0.172

AC:

14756

AN:

85632

European-Finnish (FIN)

AF:

0.144

AC:

7686

AN:

53240

Middle Eastern (MID)

AF:

0.171

AC:

984

AN:

5760

European-Non Finnish (NFE)

AF:

0.137

AC:

151409

AN:

1107552

Other (OTH)

AF:

0.153

AC:

9211

AN:

60128

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

8332

16664

24996

33328

41660

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:

0.156

AC:

23685

AN:

152264

Hom.:

1925

Cov.:

AF XY:

0.157

AC XY:

11704

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.169

AC:

7027

AN:

41548

American (AMR)

AF:

0.143

AC:

2188

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.142

AC:

493

AN:

3472

East Asian (EAS)

AF:

0.294

AC:

1521

AN:

5166

South Asian (SAS)

AF:

0.170

AC:

822

AN:

4824

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:

9521

AN:

68024

Other (OTH)

AF:

0.187

AC:

396

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1071

2141

3212

4282

5353

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

254

508

762

1016

1270

<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:

0.143

Hom.:

302

Bravo

AF:

0.157

Asia WGS

AF:

0.236

AC:

819

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 29, 2018

GeneDx

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

- -

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

-0.83

CADD

Benign

5.0

(source)

DANN

Benign

0.28

PhyloP100

0.29

PromoterAI

-0.00050

Neutral

(source)

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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