rs765235486

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PM5PP5

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 Conflicting classifications of pathogenicity,Affects (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R153C) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.000091 ( 0 hom. )

Consequence

KCTD7
NM_153033.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity; Affects criteria provided, conflicting classifications P:3U:2O:1

Conservation

PhyloP100: 9.24

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

progressive myoclonic epilepsy type 3
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
progressive myoclonus epilepsy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

KCTD7 links:

ENSG00000284461 (HGNC:):

ENSG00000284461 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-66638396-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1332794.Status of the report is criteria_provided_single_submitter, 1 stars.

PP5

Variant 7-66638396-G-A is Pathogenic according to our data. Variant chr7-66638396-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity|Affects. ClinVar VariationId is 561040.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCTD7	NM_153033.5 link	c.458G>A	p.Arg153His	missense_variant	Exon 3 of 4	ENST00000639828.2	NP_694578.1
KCTD7	NM_001167961.2 link	c.458G>A	p.Arg153His	missense_variant	Exon 3 of 5		NP_001161433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCTD7	ENST00000639828.2 link	c.458G>A	p.Arg153His	missense_variant	Exon 3 of 4	2	NM_153033.5	ENSP00000492240.1
ENSG00000284461	ENST00000503687.2 link	n.288G>A		non_coding_transcript_exon_variant	Exon 2 of 13	2		ENSP00000421074.1

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

GnomAD2 exomes

AF:

0.0000358

AC:

AN:

251354

AF XY:

0.0000368

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 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

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000128

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000107

AC:

119

AN:

1112012

Other (OTH)

AF:

0.0000166

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41464

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity; Affects

Submissions summary: Pathogenic:3Uncertain:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Progressive myoclonic epilepsy type 3

Pathogenic:2Uncertain:1Other:1

Apr 03, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: KCTD7 c.458G>A (p.Arg153His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251354 control chromosomes. c.458G>A has been reported in the literature in at-least 2 homozygous individuals, who underwent trio WES testing, and 2 compound heterozygous individuals who are affected with Progressive myoclonic epilepsy type 3 (example: Metz_2018, Binaafar_2021, Zhang_2019, Badv_2024). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34469883, 30295347, 31216804). ClinVar contains an entry for this variant (Variation ID: 561040). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Nov 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Sep 01, 2017

Baylor Genetics

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

Likely pathogenicity based on finding it once in our laboratory homozygous in a 2-year-old female with epilepsy, develomental delay, ataxia. -

Feb 25, 2019

Children’s Center Hospital, Tehran University of Medical Sciences

Significance:Affects

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Non-Syndromic Epileptic Encephalopathies (NS-EE) -

not provided

Pathogenic:1Uncertain:1

Dec 27, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30295347, 34469883, 31216804, 34866617, 38231304, 36034301, Badv2024[Article]) -

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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;.;.

PhyloP100

9.2

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

PromoterAI

-0.019

Neutral

(source)

Varity_R

0.44

gMVP

0.78

Mutation Taster

=9/91

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over