Genetic Variant KCNQ4:p.Thr501Thr (chr1-40831294-C-T) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP7

The NM_004700.4(KCNQ4):c.1503C>T(p.Thr501Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,446,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

KCNQ4
NM_004700.4 synonymous

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: -0.599

Publications

3 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: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (REVEL=0.026).

BP7

Synonymous conserved (PhyloP=-0.599 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ4	NM_004700.4 link	c.1503C>T	p.Thr501Thr	synonymous_variant	Exon 10 of 14	ENST00000347132.10	NP_004691.2	P56696-1B3KQH8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNQ4	ENST00000347132.10 link	c.1503C>T	p.Thr501Thr	synonymous_variant	Exon 10 of 14	1	NM_004700.4	ENSP00000262916.6	P56696-1
KCNQ4	ENST00000509682.6 link	c.1341C>T	p.Thr447Thr	synonymous_variant	Exon 9 of 13	5		ENSP00000423756.2	P56696-2
KCNQ4	ENST00000443478.3 link	c.1083C>T	p.Thr361Thr	synonymous_variant	Exon 9 of 13	5		ENSP00000406735.3	H0Y6N7
KCNQ4	ENST00000506017.1 link	n.822C>T		non_coding_transcript_exon_variant	Exon 7 of 11	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1446432

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

717846

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33318

American (AMR)

AF:

0.00

AC:

AN:

42130

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25704

East Asian (EAS)

AF:

0.00

AC:

AN:

39160

South Asian (SAS)

AF:

0.00

AC:

AN:

83574

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52110

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

9.05e-7

AC:

AN:

1104838

Other (OTH)

AF:

0.00

AC:

AN:

59842

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 2A

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

5.2

(source)

DANN

Benign

0.77

PhyloP100

-0.60

Mutation Taster

=100/0

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over