chr1-40835019-T-TACGAC

Variant names:

• chr1-40835019-T-TACGAC
• rs1553168601
• NM_004700.4:c.1667_1671dupACGAC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004700.4(KCNQ4):​c.1667_1671dupACGAC​(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 (★). 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
• Publications: 0 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 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 VariationId is 505873.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ4	NM_004700.4	c.1667_1671dupACGAC	p.Val558ThrfsTer3	frameshift_variant	Exon 12 of 14	ENST00000347132.10	NP_004691.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ4	ENST00000347132.10	c.1667_1671dupACGAC	p.Val558ThrfsTer3	frameshift_variant	Exon 12 of 14	1	NM_004700.4	ENSP00000262916.6
KCNQ4	ENST00000509682.6	c.1505_1509dupACGAC	p.Val504ThrfsTer3	frameshift_variant	Exon 11 of 13	5		ENSP00000423756.2
KCNQ4	ENST00000443478.3	c.1247_1251dupACGAC	p.Val418fs	frameshift_variant	Exon 11 of 13	5		ENSP00000406735.3
KCNQ4	ENST00000506017.1	n.986_990dupACGAC		non_coding_transcript_exon_variant	Exon 9 of 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

Jun 09, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3

Splicing

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

Other links and lift over

dbSNP: rs1553168601; hg19: chr1-41300691;