chr1-40819912-C-T

Position:

• chr1-40819912-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_004700.4(KCNQ4):​c.872C>T​(p.Pro291Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P291S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNQ4 NM_004700.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.91

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a intramembrane_region Pore-forming; Name=Segment H5 (size 21) in uniprot entity KCNQ4_HUMAN there are 11 pathogenic changes around while only 1 benign (92%) in NM_004700.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-40819911-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 1-40819912-C-T is Pathogenic according to our data. Variant chr1-40819912-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40819912-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-40819912-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ4	NM_004700.4	c.872C>T	p.Pro291Leu	missense_variant	6/14	ENST00000347132.10	NP_004691.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ4	ENST00000347132.10	c.872C>T	p.Pro291Leu	missense_variant	6/14	1	NM_004700.4	ENSP00000262916	P2
KCNQ4	ENST00000509682.6	c.872C>T	p.Pro291Leu	missense_variant	6/13	5		ENSP00000423756	A1
KCNQ4	ENST00000443478.3	c.560C>T	p.Pro187Leu	missense_variant	5/13	5		ENSP00000406735
KCNQ4	ENST00000506017.1	n.191C>T		non_coding_transcript_exon_variant	3/11	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 22, 2023	This variant is not present in population databases (gnomAD no frequency). 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. Experimental studies have shown that this missense change affects KCNQ4 function (PMID: 31995783, 34622280). 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. ClinVar contains an entry for this variant (Variation ID: 208370). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 23717403, 31028865). It has also been observed to segregate with disease in related individuals. This variant has been reported in individual(s) with autosomal dominant deafness (PMID: 31028865); however, the role of the variant in this condition is currently unclear. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 291 of the KCNQ4 protein (p.Pro291Leu). -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	- -

Autosomal dominant nonsyndromic hearing loss 2A Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Aug 20, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	.;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-9.4	.;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0	.;D;D
Polyphen		1.0	D;D;D
Vest4		0.99, 0.98
MutPred		0.92		Loss of ubiquitination at K289 (P = 0.0517);Loss of ubiquitination at K289 (P = 0.0517);Loss of ubiquitination at K289 (P = 0.0517);
MVP		0.99
MPC		2.3
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs797044970; hg19: chr1-41285584;