rs727504635

chr1-40818215-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004700.4(KCNQ4):c.459del(p.Ala154ProfsTer85) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNQ4 NM_004700.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.82

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 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-40818215-TC-T is Pathogenic according to our data. Variant chr1-40818215-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 179111.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-40818215-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ4	NM_004700.4	c.459del	p.Ala154ProfsTer85	frameshift_variant	3/14	ENST00000347132.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ4	ENST00000347132.10	c.459del	p.Ala154ProfsTer85	frameshift_variant	3/14	1	NM_004700.4	P2
KCNQ4	ENST00000509682.6	c.459del	p.Ala154ProfsTer85	frameshift_variant	3/13	5		A1
KCNQ4	ENST00000443478.3	c.145del	p.Ala50ProfsTer85	frameshift_variant	2/13	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 14, 2013

The Ala154fs in KCNQ4 has not been reported in individuals with hearing loss or in large population studies. This frameshift variant is predicted to alter the p rotein?s amino acid sequence beginning at position 154 and lead to a premature t ermination codon 85 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets our crite ria to be classified as pathogenic (http://pcpgm.partners.org/LMM). It should be noted that truncating mutations in the KCNQ4 gene are believed to cause dominan t late-onset hearing loss affecting high frequencies more predominantly (Nie 200 8). -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs727504635; hg19: chr1-41283887;