chr7-66629099-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_153033.5(KCTD7):c.35G>T(p.Arg12Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R12P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KCTD7
NM_153033.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.71

Publications

0 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 2 ACMG points.

PM1

In a chain BTB/POZ domain-containing protein KCTD7 (size 288) in uniprot entity KCTD7_HUMAN there are 24 pathogenic changes around while only 2 benign (92%) in NM_153033.5

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2223509).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCTD7	NM_153033.5 link	c.35G>T	p.Arg12Leu	missense_variant	Exon 1 of 4	ENST00000639828.2	NP_694578.1	Q96MP8-1A0A024RDN7
KCTD7	NM_001167961.2 link	c.35G>T	p.Arg12Leu	missense_variant	Exon 1 of 5		NP_001161433.1	Q96MP8-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCTD7	ENST00000639828.2 link	c.35G>T	p.Arg12Leu	missense_variant	Exon 1 of 4	2	NM_153033.5	ENSP00000492240.1		Q96MP8-1
ENSG00000284461	ENST00000503687.2 link	n.35G>T		non_coding_transcript_exon_variant	Exon 1 of 13	2		ENSP00000421074.1		E9PHB8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1386316

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

686554

African (AFR)

AF:

0.00

AC:

AN:

28992

American (AMR)

AF:

0.00

AC:

AN:

34410

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23908

East Asian (EAS)

AF:

0.00

AC:

AN:

32668

South Asian (SAS)

AF:

0.00

AC:

AN:

77668

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49334

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5540

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1076746

Other (OTH)

AF:

0.00

AC:

AN:

57050

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Progressive myoclonic epilepsy type 3

Uncertain:1

Mar 12, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. This variant has not been reported in the literature in individuals with KCTD7-related conditions. This sequence change replaces arginine with leucine at codon 12 of the KCTD7 protein (p.Arg12Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.020

T;.;.;.;.;.

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.89

D;D;D;D;D;D

M_CAP

Pathogenic

0.76

MetaRNN

Benign

0.22

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.;.;N;.;.

PhyloP100

3.7

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.46

.;N;.;N;.;.

REVEL

Benign

0.14

Sift

Benign

0.19

.;T;.;T;.;.

Sift4G

Benign

0.32

.;T;.;T;.;.

Polyphen

0.0040

B;.;.;.;.;.

Vest4

0.26, 0.27

MutPred

0.28

Loss of solvent accessibility (P = 0.1144);Loss of solvent accessibility (P = 0.1144);Loss of solvent accessibility (P = 0.1144);Loss of solvent accessibility (P = 0.1144);Loss of solvent accessibility (P = 0.1144);Loss of solvent accessibility (P = 0.1144);

MVP

0.61

ClinPred

0.45

GERP RS

4.0

PromoterAI

0.069

Neutral

(source)

Varity_R

0.23

gMVP

0.37

Mutation Taster

=88/12

polymorphism

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over