rs797044972

Positions:

• chr1-40822312-AGGCTGCCT-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP3 PP5

The NM_004700.4(KCNQ4):​c.1044_1051del​(p.Ala349ProfsTer19) variant causes a splice acceptor, coding sequence 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 (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNQ4 NM_004700.4 splice_acceptor, coding_sequence
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 10.0

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 6 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.042145595 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7, offset of 0 (no position change), new splice context is: cacgtcccccataccaccAGgcg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 1-40822312-AGGCTGCCT-A is Pathogenic according to our data. Variant chr1-40822312-AGGCTGCCT-A is described in ClinVar as [Pathogenic]. Clinvar id is 208372.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-40822312-AGGCTGCCT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ4	NM_004700.4	c.1044_1051del	p.Ala349ProfsTer19	splice_acceptor_variant, coding_sequence_variant	8/14	ENST00000347132.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ4	ENST00000347132.10	c.1044_1051del	p.Ala349ProfsTer19	splice_acceptor_variant, coding_sequence_variant	8/14	1	NM_004700.4	P2
KCNQ4	ENST00000443478.3	c.730_737del	p.Ala245ProfsTer19	splice_acceptor_variant, coding_sequence_variant	7/13	5
KCNQ4	ENST00000509682.6	c.1044_1051del	p.Ala349ProfsTer19	splice_acceptor_variant, coding_sequence_variant	8/13	5		A1
KCNQ4	ENST00000506017.1	n.363_370del		splice_acceptor_variant, non_coding_transcript_exon_variant	5/11	2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

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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: rs797044972; hg19: chr1-41287984;