rs745917176
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4
The NM_153033.5(KCTD7):c.506G>A(p.Arg169Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000083 in 1,613,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000088 ( 0 hom. )
Consequence
KCTD7
NM_153033.5 missense
NM_153033.5 missense
Scores
2
3
6
Clinical Significance
Conservation
PhyloP100: 9.07
Genes affected
KCTD7 (HGNC:21957): (potassium channel tetramerization domain containing 7) This gene encodes a member of the potassium channel tetramerization domain-containing protein family. Family members are identified on a structural basis and contain an amino-terminal domain similar to the T1 domain present in the voltage-gated potassium channel. Mutations in this gene have been associated with progressive myoclonic epilepsy-3. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Jan 2011]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM1
In a chain BTB/POZ domain-containing protein KCTD7 (size 288) in uniprot entity KCTD7_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_153033.5
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.33467355).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCTD7 | NM_153033.5 | c.506G>A | p.Arg169Gln | missense_variant | 4/4 | ENST00000639828.2 | NP_694578.1 | |
KCTD7 | NM_001167961.2 | c.506G>A | p.Arg169Gln | missense_variant | 4/5 | NP_001161433.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCTD7 | ENST00000639828.2 | c.506G>A | p.Arg169Gln | missense_variant | 4/4 | 2 | NM_153033.5 | ENSP00000492240 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152164Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
5
AN:
152164
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251132Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135788
GnomAD3 exomes
AF:
AC:
7
AN:
251132
Hom.:
AF XY:
AC XY:
6
AN XY:
135788
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000882 AC: 129AN: 1461788Hom.: 0 Cov.: 32 AF XY: 0.0000880 AC XY: 64AN XY: 727206
GnomAD4 exome
AF:
AC:
129
AN:
1461788
Hom.:
Cov.:
32
AF XY:
AC XY:
64
AN XY:
727206
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152164Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74332
GnomAD4 genome
AF:
AC:
5
AN:
152164
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
74332
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
0
ALSPAC
AF:
AC:
2
ExAC
AF:
AC:
3
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Aug 11, 2017 | - - |
Progressive myoclonic epilepsy type 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 07, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 169 of the KCTD7 protein (p.Arg169Gln). This variant is present in population databases (rs745917176, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with KCTD7-related conditions. ClinVar contains an entry for this variant (Variation ID: 423509). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 10, 2017 | A variant of uncertain significance has been identified in the KCTD7 gene. The R169Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R169Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R169Q variant is a a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Benign
T
MutationTaster
Benign
D
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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