rs80358276

Positions:

• chr1-40819459-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_004700.4(KCNQ4):​c.821T>A​(p.Leu274His) 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 Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L274L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KCNQ4 NM_004700.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 8.02

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_004700.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 1-40819459-T-A is Pathogenic according to our data. Variant chr1-40819459-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 6247.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-40819459-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ4	NM_004700.4	c.821T>A	p.Leu274His	missense_variant	5/14	ENST00000347132.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ4	ENST00000347132.10	c.821T>A	p.Leu274His	missense_variant	5/14	1	NM_004700.4	P2
KCNQ4	ENST00000509682.6	c.821T>A	p.Leu274His	missense_variant	5/13	5		A1
KCNQ4	ENST00000443478.3	c.509T>A	p.Leu170His	missense_variant	4/13	5
KCNQ4	ENST00000506017.1	n.140T>A		non_coding_transcript_exon_variant	2/11	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 2A Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	Aug 20, 2015	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 14, 2011	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.98	D;D;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;H;H
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.93	D
Polyphen		1.0	D;D;D
Vest4		0.99, 0.97
MutPred		0.91		Loss of stability (P = 0.0119);Loss of stability (P = 0.0119);Loss of stability (P = 0.0119);
MVP		1.0
MPC		2.6
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.96
gMVP		0.99

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: rs80358276; hg19: chr1-41285131;