chr1-40838421-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_004700.4(KCNQ4):c.1986C>G(p.Pro662Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,614,138 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00096 ( 28 hom. )

Consequence

KCNQ4
NM_004700.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.24

Publications

2 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.036).

BP6

Variant 1-40838421-C-G is Benign according to our data. Variant chr1-40838421-C-G is described in ClinVar as Benign. ClinVar VariationId is 226687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.24 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00144 (220/152356) while in subpopulation EAS AF = 0.0353 (183/5182). AF 95% confidence interval is 0.0311. There are 1 homozygotes in GnomAd4. There are 103 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 28 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
KCNQ4	NM_004700.4 link	c.1986C>G	p.Pro662Pro	synonymous_variant	Exon 14 of 14	ENST00000347132.10	NP_004691.2
KCNQ4	NM_172163.3 link	c.1824C>G	p.Pro608Pro	synonymous_variant	Exon 13 of 13		NP_751895.1
KCNQ4	XM_017002792.2 link	c.969C>G	p.Pro323Pro	synonymous_variant	Exon 11 of 11		XP_016858281.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
KCNQ4	ENST00000347132.10 link	c.1986C>G	p.Pro662Pro	synonymous_variant	Exon 14 of 14	1	NM_004700.4	ENSP00000262916.6
KCNQ4	ENST00000509682.6 link	c.1824C>G	p.Pro608Pro	synonymous_variant	Exon 13 of 13	5		ENSP00000423756.2
KCNQ4	ENST00000443478.3 link	c.1566C>G	p.Pro522Pro	synonymous_variant	Exon 13 of 13	5		ENSP00000406735.3
KCNQ4	ENST00000506017.1 link	n.1305C>G		non_coding_transcript_exon_variant	Exon 11 of 11	2

Frequencies

GnomAD3 genomes

AF:

0.00145

AC:

221

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0354

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00304

AC:

763

AN:

251192

AF XY:

0.00297

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0394

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000959

AC:

1402

AN:

1461782

Hom.:

Cov.:

AF XY:

0.000949

AC XY:

690

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.0000671

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.0283

AC:

1124

AN:

39694

South Asian (SAS)

AF:

0.000997

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000180

AC:

AN:

1111942

Other (OTH)

AF:

0.00278

AC:

168

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

183

274

366

457

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.00144

AC:

220

AN:

152356

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

103

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41578

American (AMR)

AF:

0.00111

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0353

AC:

183

AN:

5182

South Asian (SAS)

AF:

0.00269

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68040

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000470

Hom.:

Bravo

AF:

0.00164

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 14, 2018

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.

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Benign:1

Jul 05, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Pro662Pro in exon 14 of KCNQ4: This variant is not expected to have clinical s ignificance because it been identified in 4% (350/8624) East Asian chromosomes b y the Exome Aggregation Consortium (http://exac.broadinstitute.org; dbSNP rs1916 31836), and because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence.

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

-0.52

CADD

Benign

4.3

(source)

DANN

Benign

0.77

PhyloP100

-2.2

Mutation Taster

=97/3

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