rs2361660

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.708+14G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.693 in 1,581,178 control chromosomes in the GnomAD database, including 384,137 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.66 ( 33430 hom., cov: 32)

Exomes 𝑓: 0.70 ( 350707 hom. )

Consequence

KCNQ4
NM_004700.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.0700

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
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=-0.85).

BP6

Variant 1-40818694-G-C is Benign according to our data. Variant chr1-40818694-G-C is described in ClinVar as Benign. ClinVar VariationId is 45104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.725 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004700.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ4	NM_004700.4	MANE Select	c.708+14G>C		intron	N/A	NP_004691.2
	KCNQ4	NM_172163.3		c.708+14G>C		intron	N/A	NP_751895.1	P56696-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KCNQ4	ENST00000347132.10	TSL:1 MANE Select	c.708+14G>C	intron	N/A	ENSP00000262916.6	P56696-1
KCNQ4	ENST00000967337.1		c.708+14G>C	intron	N/A	ENSP00000637396.1
KCNQ4	ENST00000967338.1		c.708+14G>C	intron	N/A	ENSP00000637397.1

Frequencies

GnomAD3 genomes

AF:

0.657

AC:

99842

AN:

151884

Hom.:

33414

Cov.:

show subpopulations

Gnomad AFR

AF:

0.592

Gnomad AMI

AF:

0.761

Gnomad AMR

AF:

0.555

Gnomad ASJ

AF:

0.669

Gnomad EAS

AF:

0.455

Gnomad SAS

AF:

0.569

Gnomad FIN

AF:

0.716

Gnomad MID

AF:

0.699

Gnomad NFE

AF:

0.730

Gnomad OTH

AF:

0.661

GnomAD2 exomes

AF:

0.643

AC:

124402

AN:

193618

AF XY:

0.647

show subpopulations

Gnomad AFR exome

AF:

0.590

Gnomad AMR exome

AF:

0.519

Gnomad ASJ exome

AF:

0.670

Gnomad EAS exome

AF:

0.468

Gnomad FIN exome

AF:

0.720

Gnomad NFE exome

AF:

0.727

Gnomad OTH exome

AF:

0.669

GnomAD4 exome

AF:

0.697

AC:

995938

AN:

1429174

Hom.:

350707

Cov.:

AF XY:

0.694

AC XY:

492785

AN XY:

709718

show subpopulations

African (AFR)

AF:

0.591

AC:

19408

AN:

32818

American (AMR)

AF:

0.525

AC:

21486

AN:

40940

Ashkenazi Jewish (ASJ)

AF:

0.665

AC:

17092

AN:

25690

East Asian (EAS)

AF:

0.415

AC:

15793

AN:

38044

South Asian (SAS)

AF:

0.575

AC:

48057

AN:

83536

European-Finnish (FIN)

AF:

0.734

AC:

31870

AN:

43428

Middle Eastern (MID)

AF:

0.685

AC:

3280

AN:

4788

European-Non Finnish (NFE)

AF:

0.726

AC:

798732

AN:

1100656

Other (OTH)

AF:

0.679

AC:

40220

AN:

59274

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

16009

32018

48028

64037

80046

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19706

39412

59118

78824

98530

<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:

0.657

AC:

99896

AN:

152004

Hom.:

33430

Cov.:

AF XY:

0.653

AC XY:

48467

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.592

AC:

24571

AN:

41490

American (AMR)

AF:

0.555

AC:

8475

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.669

AC:

2321

AN:

3470

East Asian (EAS)

AF:

0.454

AC:

2314

AN:

5096

South Asian (SAS)

AF:

0.569

AC:

2741

AN:

4816

European-Finnish (FIN)

AF:

0.716

AC:

7571

AN:

10578

Middle Eastern (MID)

AF:

0.697

AC:

205

AN:

294

European-Non Finnish (NFE)

AF:

0.730

AC:

49605

AN:

67958

Other (OTH)

AF:

0.664

AC:

1402

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1737

3475

5212

6950

8687

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

794

1588

2382

3176

3970

<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:

0.703

Hom.:

6966

Bravo

AF:

0.642

Asia WGS

AF:

0.540

AC:

1880

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (3)

Autosomal dominant nonsyndromic hearing loss 2A (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

3.7

(source)

DANN

Benign

0.36

PhyloP100

0.070

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over