rs34287852

Positions:

• chr1-40831156-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004700.4(KCNQ4):​c.1365T>G​(p.His455Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 1,609,926 control chromosomes in the GnomAD database, including 40,609 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2747 hom., cov: 32)
  • Exomes 𝑓: 0.22 (37862 hom.)
• Consequence: KCNQ4 NM_004700.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0130

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013206303).
• BP6: Variant 1-40831156-T-G is Benign according to our data. Variant chr1-40831156-T-G is described in ClinVar as [Benign]. Clinvar id is 45101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40831156-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.241 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ4	NM_004700.4	c.1365T>G	p.His455Gln	missense_variant	10/14	ENST00000347132.10	NP_004691.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ4	ENST00000347132.10	c.1365T>G	p.His455Gln	missense_variant	10/14	1	NM_004700.4	ENSP00000262916.6
KCNQ4	ENST00000509682.6	c.1203T>G	p.His401Gln	missense_variant	9/13	5		ENSP00000423756.2
KCNQ4	ENST00000443478.3	c.945T>G	p.His315Gln	missense_variant	9/13	5		ENSP00000406735.3
KCNQ4	ENST00000506017.1	n.684T>G		non_coding_transcript_exon_variant	7/11	2

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25408 AN: 151972 Hom.: 2746 Cov.: 32

Gnomad AFR AF: 0.0431

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.0601

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.264

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.245

Gnomad OTH AF: 0.165

GnomAD3 exomes AF: 0.176 AC: 42379 AN: 240294 Hom.: 4324 AF XY: 0.181 AC XY: 23565 AN XY: 130440

Gnomad AFR exome AF: 0.0360

Gnomad AMR exome AF: 0.0987

Gnomad ASJ exome AF: 0.163

Gnomad EAS exome AF: 0.0639

Gnomad SAS exome AF: 0.127

Gnomad FIN exome AF: 0.256

Gnomad NFE exome AF: 0.239

Gnomad OTH exome AF: 0.195

GnomAD4 exome AF: 0.221 AC: 322064 AN: 1457836 Hom.: 37862 Cov.: 37 AF XY: 0.219 AC XY: 158757 AN XY: 724852

Gnomad4 AFR exome AF: 0.0337

Gnomad4 AMR exome AF: 0.106

Gnomad4 ASJ exome AF: 0.167

Gnomad4 EAS exome AF: 0.0492

Gnomad4 SAS exome AF: 0.129

Gnomad4 FIN exome AF: 0.261

Gnomad4 NFE exome AF: 0.245

Gnomad4 OTH exome AF: 0.205

GnomAD4 genome AF: 0.167 AC: 25413 AN: 152090 Hom.: 2747 Cov.: 32 AF XY: 0.165 AC XY: 12253 AN XY: 74344

Gnomad4 AFR AF: 0.0430

Gnomad4 AMR AF: 0.140

Gnomad4 ASJ AF: 0.167

Gnomad4 EAS AF: 0.0598

Gnomad4 SAS AF: 0.128

Gnomad4 FIN AF: 0.264

Gnomad4 NFE AF: 0.245

Gnomad4 OTH AF: 0.169

Alfa AF: 0.218 Hom.: 4840

Bravo AF: 0.153

TwinsUK AF: 0.255 AC: 947

ALSPAC AF: 0.253 AC: 976

ESP6500AA AF: 0.0488 AC: 215

ESP6500EA AF: 0.240 AC: 2062

ExAC AF: 0.173 AC: 20979

Asia WGS AF: 0.111 AC: 388 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2017	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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	His455Gln in Exon 10 of KCNQ4: This variant is not expected to have clinical sig nificance because it has been identified in 24.0% (1685/7018) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs34287852). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Autosomal dominant nonsyndromic hearing loss 2A Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Benign	0.19	T;T;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.75	.;T;T
MetaRNN	Benign	0.0013	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.14	N;N;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.1	.;N;N
REVEL	Uncertain	0.29
Sift	Benign	0.54	.;T;T
Sift4G	Benign	0.40	.;T;T
Polyphen		0.022	B;B;B
Vest4		0.099, 0.21
MutPred		0.20		Gain of MoRF binding (P = 0.0966);Gain of MoRF binding (P = 0.0966);.;
MPC		0.13
ClinPred		0.0016	T
GERP RS		2.0
Varity_R		0.057
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs34287852; hg19: chr1-41296828; COSMIC: COSV61273114;