rs765235486

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The NM_153033.5(KCTD7):c.458G>A(p.Arg153His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000843 in 1,614,120 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic,Affects (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000091 ( 0 hom. )

Consequence

KCTD7
NM_153033.5 missense

Scores

Clinical Significance

Likely pathogenic; Affects criteria provided, multiple submitters, no conflicts P:2U:1O:1

Conservation

PhyloP100: 9.24

Variant links:

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]

KCTD7 links:

ENSG00000284461 (HGNC:):

ENSG00000284461 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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;

PP5

Variant 7-66638396-G-A is Pathogenic according to our data. Variant chr7-66638396-G-A is described in ClinVar as [Likely_pathogenic, Affects]. Clinvar id is 561040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCTD7	NM_153033.5 linkuse as main transcript	c.458G>A	p.Arg153His	missense_variant	3/4	ENST00000639828.2	NP_694578.1	Q96MP8-1A0A024RDN7
KCTD7	NM_001167961.2 linkuse as main transcript	c.458G>A	p.Arg153His	missense_variant	3/5		NP_001161433.1	Q96MP8-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCTD7	ENST00000639828.2 linkuse as main transcript	c.458G>A	p.Arg153His	missense_variant	3/4	2	NM_153033.5	ENSP00000492240.1		Q96MP8-1
ENSG00000284461	ENST00000503687.2 linkuse as main transcript	n.288G>A		non_coding_transcript_exon_variant	2/13	2		ENSP00000421074.1		E9PHB8

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251354

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000910

AC:

133

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000107

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Likely pathogenic; Affects

Submissions summary: Pathogenic:2Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Progressive myoclonic epilepsy type 3

Pathogenic:1Uncertain:1Other:1

Uncertain significance, flagged submission	clinical testing	Baylor Genetics	Sep 01, 2017	Likely pathogenicity based on finding it once in our laboratory homozygous in a 2-year-old female with epilepsy, develomental delay, ataxia. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 153 of the KCTD7 protein (p.Arg153His). This variant is present in population databases (rs765235486, gnomAD 0.01%). This missense change has been observed in individuals with progressive myoclonic epilepsy (PMID: 30295347, 31216804, 34469883, 36034301). ClinVar contains an entry for this variant (Variation ID: 561040). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCTD7 protein function. This variant disrupts the p.Arg153 amino acid residue in KCTD7. Other variant(s) that disrupt this residue have been observed in individuals with KCTD7-related conditions (PMID: 34866617), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Affects, criteria provided, single submitter	clinical testing	Children’s Center Hospital, Tehran University of Medical Sciences	Feb 25, 2019	Non-Syndromic Epileptic Encephalopathies (NS-EE) -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.34

T;.;.;.;.

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

D;D;D;D;D

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.74

D;D;D;D;D

MetaSVM

Uncertain

0.12

MutationAssessor

Uncertain

2.2

M;.;M;.;.

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-4.6

.;.;D;.;.

REVEL

Uncertain

0.64

Sift

Uncertain

0.0020

.;.;D;.;.

Sift4G

Uncertain

0.017

.;.;D;.;.

Polyphen

0.94

P;.;.;.;.

Vest4

0.91

MutPred

0.46

Gain of ubiquitination at K148 (P = 0.0505);Gain of ubiquitination at K148 (P = 0.0505);Gain of ubiquitination at K148 (P = 0.0505);Gain of ubiquitination at K148 (P = 0.0505);Gain of ubiquitination at K148 (P = 0.0505);

MVP

0.94

ClinPred

0.53

GERP RS

5.9

Varity_R

0.44

gMVP

0.78

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over