rs773015201

chr1-40819949-C-Achr1-40819949-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_004700.4(KCNQ4):c.909C>A(p.Phe303Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F303F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNQ4 NM_004700.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.312

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a helix (size 41) in uniprot entity KCNQ4_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_004700.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.826

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ4	NM_004700.4	c.909C>A	p.Phe303Leu	missense_variant	6/14	ENST00000347132.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ4	ENST00000347132.10	c.909C>A	p.Phe303Leu	missense_variant	6/14	1	NM_004700.4	P2
KCNQ4	ENST00000509682.6	c.909C>A	p.Phe303Leu	missense_variant	6/13	5		A1
KCNQ4	ENST00000443478.3	c.597C>A	p.Phe199Leu	missense_variant	5/13	5
KCNQ4	ENST00000506017.1	n.228C>A		non_coding_transcript_exon_variant	3/11	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461862 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;D;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.66	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.59	N;N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
Polyphen		1.0	D;D;D
Vest4		0.90, 0.88
MutPred		0.59		Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP		0.98
MPC		2.5
ClinPred		0.98	D
GERP RS		0.89
Varity_R		0.87
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs773015201; hg19: chr1-41285621;