rs727505133
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_004700.4(KCNQ4):āc.1954C>Gā(p.Leu652Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,720 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: not found (cov: 33)
Exomes š: 6.8e-7 ( 0 hom. )
Consequence
KCNQ4
NM_004700.4 missense
NM_004700.4 missense
Scores
9
10
Clinical Significance
Conservation
PhyloP100: 2.18
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 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ4 | NM_004700.4 | c.1954C>G | p.Leu652Val | missense_variant | 14/14 | ENST00000347132.10 | |
KCNQ4 | NM_172163.3 | c.1792C>G | p.Leu598Val | missense_variant | 13/13 | ||
KCNQ4 | XM_017002792.2 | c.937C>G | p.Leu313Val | missense_variant | 11/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ4 | ENST00000347132.10 | c.1954C>G | p.Leu652Val | missense_variant | 14/14 | 1 | NM_004700.4 | P2 | |
KCNQ4 | ENST00000509682.6 | c.1792C>G | p.Leu598Val | missense_variant | 13/13 | 5 | A1 | ||
KCNQ4 | ENST00000443478.3 | c.1537C>G | p.Leu513Val | missense_variant | 13/13 | 5 | |||
KCNQ4 | ENST00000506017.1 | n.1273C>G | non_coding_transcript_exon_variant | 11/11 | 2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461720Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727190
GnomAD4 exome
AF:
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1
AN:
1461720
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
727190
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 19, 2014 | The Leu652Val variant in KCNQ4 has not been reported in individuals with hearing loss or in large population studies. Computational prediction tools and conserv ation analyses do not provide strong support for or against an impact to the pro tein. In summary, the clinical significance of this variant is uncertain. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
.;N;N
REVEL
Uncertain
Sift
Benign
.;D;D
Sift4G
Benign
.;T;T
Polyphen
D;D;P
Vest4
0.095, 0.33
MutPred
Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);.;
MVP
0.88
MPC
2.1
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at