7-66629099-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_153033.5(KCTD7):c.35G>C(p.Arg12Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000013 in 1,538,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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. R12L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

KCTD7
NM_153033.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.71

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a chain BTB/POZ domain-containing protein KCTD7 (size 288) in uniprot entity KCTD7_HUMAN there are 29 pathogenic changes around while only 4 benign (88%) in NM_153033.5

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18995824).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCTD7	NM_153033.5 linkuse as main transcript	c.35G>C	p.Arg12Pro	missense_variant	1/4	ENST00000639828.2
KCTD7	NM_001167961.2 linkuse as main transcript	c.35G>C	p.Arg12Pro	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCTD7	ENST00000639828.2 linkuse as main transcript	c.35G>C	p.Arg12Pro	missense_variant	1/4	2	NM_153033.5	A1	Q96MP8-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151922

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000616

AC:

AN:

162444

Hom.:

AF XY:

0.0000112

AC XY:

AN XY:

89238

show subpopulations

Gnomad AFR exome

AF:

0.000141

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.21e-7

AC:

AN:

1386316

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

686554

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.29e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151922

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74206

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000253

AC:

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 21, 2020

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. 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. This variant has not been reported in the literature in individuals with KCTD7-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces arginine with proline at codon 12 of the KCTD7 protein (p.Arg12Pro). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and proline. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.27

Cadd

Uncertain

Dann

Benign

0.96

DEOGEN2

Benign

0.017

T;.;.;.;.;.

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.86

D;D;D;D;D;D

M_CAP

Pathogenic

0.77

MetaRNN

Benign

0.19

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.;.;N;.;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.93

Polyphen

0.016

B;.;.;.;.;.

Vest4

0.26, 0.27

MutPred

0.29

Loss of stability (P = 0.0627);Loss of stability (P = 0.0627);Loss of stability (P = 0.0627);Loss of stability (P = 0.0627);Loss of stability (P = 0.0627);Loss of stability (P = 0.0627);

MVP

0.61

ClinPred

0.22

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.28

gMVP

0.41

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