chr4-44448360-T-G
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_198353.3(KCTD8):āc.164A>Cā(p.Tyr55Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,593,306 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 (ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 32)
Exomes š: 0.000010 ( 0 hom. )
Consequence
KCTD8
NM_198353.3 missense
NM_198353.3 missense
Scores
12
6
1
Clinical Significance
Conservation
PhyloP100: 7.81
Genes affected
KCTD8 (HGNC:22394): (potassium channel tetramerization domain containing 8) Predicted to be involved in regulation of G protein-coupled receptor signaling pathway. Predicted to be located in cell projection; postsynaptic membrane; and presynaptic membrane. Predicted to be integral component of membrane. Predicted to be part of receptor complex. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.96
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCTD8 | NM_198353.3 | c.164A>C | p.Tyr55Ser | missense_variant | 1/2 | ENST00000360029.4 | |
KCTD8 | XM_011513690.4 | c.164A>C | p.Tyr55Ser | missense_variant | 1/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCTD8 | ENST00000360029.4 | c.164A>C | p.Tyr55Ser | missense_variant | 1/2 | 1 | NM_198353.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151562Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.0000104 AC: 15AN: 1441744Hom.: 0 Cov.: 32 AF XY: 0.0000126 AC XY: 9AN XY: 716008
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GnomAD4 genome AF: 0.0000132 AC: 2AN: 151562Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74006
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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 | Ambry Genetics | Nov 10, 2022 | The c.164A>C (p.Y55S) alteration is located in exon 1 (coding exon 1) of the KCTD8 gene. This alteration results from a A to C substitution at nucleotide position 164, causing the tyrosine (Y) at amino acid position 55 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of disorder (P = 0.0057);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at