rs1553168601

chr1-40835019-T-TACGAC

Variant summary

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

The NM_004700.4(KCNQ4):c.1667_1671dup(p.Val558ThrfsTer3) 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 Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y556Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KCNQ4 NM_004700.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.32

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 1-40835019-T-TACGAC is Pathogenic according to our data. Variant chr1-40835019-T-TACGAC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 505873.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ4	NM_004700.4	c.1667_1671dup	p.Val558ThrfsTer3	frameshift_variant	12/14	ENST00000347132.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ4	ENST00000347132.10	c.1667_1671dup	p.Val558ThrfsTer3	frameshift_variant	12/14	1	NM_004700.4	P2
KCNQ4	ENST00000443478.3	c.1248_1252dup	p.Val419ThrfsTer3	frameshift_variant	11/13	5
KCNQ4	ENST00000509682.6	c.1505_1509dup	p.Val504ThrfsTer3	frameshift_variant	11/13	5		A1
KCNQ4	ENST00000506017.1	n.986_990dup		non_coding_transcript_exon_variant	9/11	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 09, 2017

The p.Val558ThrfsX3 (NM_004700.3 c.1671_1672insACGAC) variant in KCNQ4 has not b een previously reported in individuals with hearing loss and is absent from larg e population studies. This variant is predicted to cause a frameshift, which alt ers the protein?s amino acid sequence beginning at position 558 and leads to a p remature termination codon 3 amino acids downstream. This alteration is then pre dicted to lead to a truncated or absent protein. Heterozygous loss of function o f the KCNQ4 gene is an established disease mechanism in hearing loss. In summary , although additional studies are required to fully establish its clinical signi ficance, the p.Val558ThrfsX3 variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553168601; hg19: chr1-41300691;