1-40819897-A-G

Position:

• chr1-40819897-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_004700.4(KCNQ4):​c.857A>G​(p.Tyr286Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,696 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y286S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: KCNQ4 NM_004700.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U: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 10 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_004700.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-40819897-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1184480.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ4	NM_004700.4	c.857A>G	p.Tyr286Cys	missense_variant	6/14	ENST00000347132.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ4	ENST00000347132.10	c.857A>G	p.Tyr286Cys	missense_variant	6/14	1	NM_004700.4	P2
KCNQ4	ENST00000509682.6	c.857A>G	p.Tyr286Cys	missense_variant	6/13	5		A1
KCNQ4	ENST00000443478.3	c.545A>G	p.Tyr182Cys	missense_variant	5/13	5
KCNQ4	ENST00000506017.1	n.176A>G		non_coding_transcript_exon_variant	3/11	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461696 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727170

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 03, 2016

The p.Tyr286Cys variant in KCNQ4 has not been previously reported in individuals with hearing loss and was absent from large population studies. Computational p rediction tools and conservation analysis suggest that this variant may impact t he protein. In addition, this variant occurs in the highly conserved pore formin g region (P-loop) of the KCNQ4 protein, and several causative missense variants in this region have been reported in affected families and were shown to impact normal protein function (Gao 2013). However, this information is not predictive enough to determine pathogenicity for this variant. In summary, the clinical sig nificance of the p.Tyr286Cys variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	.;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H;H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-8.4	.;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0	.;D;D
Polyphen		1.0	D;D;D
Vest4		0.99, 0.95
MutPred		0.75		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.99
MPC		2.5
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.97
gMVP		1.0

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: rs876657841; hg19: chr1-41285569;