rs191631836

Positions:

chr1-40838421-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_004700.4(KCNQ4):c.1986C>G(p.Pro662=) 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

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

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 220 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KCNQ4	NM_004700.4 linkuse as main transcript	c.1986C>G	p.Pro662=	synonymous_variant	14/14	ENST00000347132.10	NP_004691.2
KCNQ4	NM_172163.3 linkuse as main transcript	c.1824C>G	p.Pro608=	synonymous_variant	13/13		NP_751895.1
KCNQ4	XM_017002792.2 linkuse as main transcript	c.969C>G	p.Pro323=	synonymous_variant	11/11		XP_016858281.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ4	ENST00000347132.10 linkuse as main transcript	c.1986C>G	p.Pro662=	synonymous_variant	14/14	1	NM_004700.4	ENSP00000262916	P2	P56696-1
KCNQ4	ENST00000509682.6 linkuse as main transcript	c.1824C>G	p.Pro608=	synonymous_variant	13/13	5		ENSP00000423756	A1	P56696-2
KCNQ4	ENST00000443478.3 linkuse as main transcript	c.1569C>G	p.Pro523=	synonymous_variant	13/13	5		ENSP00000406735
KCNQ4	ENST00000506017.1 linkuse as main transcript	n.1305C>G		non_coding_transcript_exon_variant	11/11	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

GnomAD3 exomes

AF:

0.00304

AC:

763

AN:

251192

Hom.:

AF XY:

0.00297

AC XY:

403

AN XY:

135806

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 SAS exome

AF:

0.000882

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

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0283

Gnomad4 SAS exome

AF:

0.000997

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.00278

GnomAD4 genome

AF:

0.00144

AC:

220

AN:

152356

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

103

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0353

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00189

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 05, 2015

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

4.3

DANN

Benign

0.77

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over