1-40837720-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_004700.4(KCNQ4):​c.1801G>T​(p.Asp601Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D601D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

KCNQ4
NM_004700.4 missense

Scores

4
7
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.58
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.802

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNQ4NM_004700.4 linkc.1801G>T p.Asp601Tyr missense_variant Exon 13 of 14 ENST00000347132.10 NP_004691.2 P56696-1B3KQH8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNQ4ENST00000347132.10 linkc.1801G>T p.Asp601Tyr missense_variant Exon 13 of 14 1 NM_004700.4 ENSP00000262916.6 P56696-1
KCNQ4ENST00000509682.6 linkc.1639G>T p.Asp547Tyr missense_variant Exon 12 of 13 5 ENSP00000423756.2 P56696-2
KCNQ4ENST00000443478.3 linkc.1381G>T p.Asp461Tyr missense_variant Exon 12 of 13 5 ENSP00000406735.3 H0Y6N7
KCNQ4ENST00000506017.1 linkn.1120G>T non_coding_transcript_exon_variant Exon 10 of 11 2

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461056
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
726758
show subpopulations
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:
0.00000270
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
31
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 05, 2015
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Asp601Tyr variant in KCNQ4 has not been previously reported in individuals with hearing loss or in large population studies. Computational prediction tool s and conservation analysis do not provide strong support for or against an impa ct to the protein. In summary, the clinical significance of the p.Asp601Tyr vari ant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Uncertain
0.050
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.73
D;D;.
Eigen
Uncertain
0.36
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.92
.;D;D
M_CAP
Benign
0.085
D
MetaRNN
Pathogenic
0.80
D;D;D
MetaSVM
Benign
-0.77
T
MutationAssessor
Benign
1.4
L;L;.
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
-2.2
.;N;N
REVEL
Pathogenic
0.77
Sift
Benign
0.049
.;D;T
Sift4G
Benign
0.073
.;T;T
Polyphen
1.0
D;D;D
Vest4
0.37, 0.36
MutPred
0.50
Gain of phosphorylation at D601 (P = 0.0082);Gain of phosphorylation at D601 (P = 0.0082);.;
MVP
0.80
MPC
2.3
ClinPred
0.93
D
GERP RS
4.9
Varity_R
0.36
gMVP
0.40

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs876657838; hg19: chr1-41303392; API