NM_004700.4:c.961G>A

Variant names:

• chr1-40820180-G-A
• rs28939710
• NM_004700.4:c.961G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_004700.4(KCNQ4):​c.961G>A​(p.Gly321Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: KCNQ4 NM_004700.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 10.0
• Publications: 17 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953
• PP5: Variant 1-40820180-G-A is Pathogenic according to our data. Variant chr1-40820180-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 6243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ4	NM_004700.4	c.961G>A	p.Gly321Ser	missense_variant	Exon 7 of 14	ENST00000347132.10	NP_004691.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ4	ENST00000347132.10	c.961G>A	p.Gly321Ser	missense_variant	Exon 7 of 14	1	NM_004700.4	ENSP00000262916.6
KCNQ4	ENST00000509682.6	c.961G>A	p.Gly321Ser	missense_variant	Exon 7 of 13	5		ENSP00000423756.2
KCNQ4	ENST00000443478.3	c.646G>A	p.Gly216Ser	missense_variant	Exon 6 of 13	5		ENSP00000406735.3
KCNQ4	ENST00000506017.1	n.280G>A		non_coding_transcript_exon_variant	Exon 4 of 11	2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74344

African (AFR) AF: 0.00 AC: 0 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 2A Pathogenic:4

Aug 20, 2015

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 22, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 26, 2019

Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

- -

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Apr 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 321 of the KCNQ4 protein (p.Gly321Ser). This variant is present in population databases (rs28939710, gnomAD 0.007%). This missense change has been observed in individuals with autosomal dominant deafness (PMID: 10369879, 34824372, 36344503; Invitae). ClinVar contains an entry for this variant (Variation ID: 6243). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ4 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ4 function (PMID: 20966080, 23750663, 26515070). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Dec 01, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate p.(G321S) results in non-functional channels and significantly reduces KCNQ4 trafficking (Kim et al., 2011; Gao et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34316018, 28340560, 23399560, 25525159, 31541171, 21951272, 26036578, 9126484, 8035838, 27619418, 18797286, 23776385, 25116015, 23717403, 11556850, 30556268, 27704564, 17033161, 36140355, 12408061, 24616153, 11252765, 28802383, Zhang2021[Review], 26515070, 10369879, 34824372, 34732400, 20966080, 23750663) -

Rare genetic deafness Pathogenic:1

Oct 14, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly321Ser variant in KCNQ4 has been previously reported to segregate with autosomal dominant hearing loss in multiple individuals from a large Dutch family (Coucke 1999 PMID: 10369879, Van Camp 1997 PMID: 9126484). It has also been identified in 0.006% (1/15414) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is present in ClinVar (Variation ID 6243). Functional studies indicate that the variant results in a dominant negative effect (Leitner 2012 PMID: 21951272, Gao 2013 PMID: 23750663), and computational tools and conservation analyses also suggest an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hearing loss. ACMG/AMP Criteria applied: PP1_Moderate, PM2, PP3, PS3_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;D;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	.;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.4	M;M;M
PhyloP100		10
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.5	.;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.021	.;D;D
Sift4G	Uncertain	0.041	.;D;D
Polyphen		1.0	D;D;D
Vest4		0.93, 0.91
MutPred		0.81		Loss of glycosylation at S320 (P = 0.0241);Loss of glycosylation at S320 (P = 0.0241);Loss of glycosylation at S320 (P = 0.0241);
MVP		1.0
MPC		2.3
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.76
gMVP		0.93
Mutation Taster		=20/80	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs28939710; hg19: chr1-41285852;