Genetic Variant KCTD7:p.Thr5Met (chr7-66629078-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_153033.5(KCTD7):c.14C>T(p.Thr5Met) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T5R) 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

Not reported in ClinVar

Conservation

PhyloP100: 3.91

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 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=0.28893882).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCTD7	NM_153033.5 link	c.14C>T	p.Thr5Met	missense_variant	Exon 1 of 4	ENST00000639828.2	NP_694578.1	Q96MP8-1A0A024RDN7
KCTD7	NM_001167961.2 link	c.14C>T	p.Thr5Met	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.14C>T	p.Thr5Met	missense_variant	Exon 1 of 4	2	NM_153033.5	ENSP00000492240.1		Q96MP8-1
ENSG00000284461	ENST00000503687.2 link	n.14C>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:

1374938

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

679868

African (AFR)

AF:

0.00

AC:

AN:

28804

American (AMR)

AF:

0.00

AC:

AN:

32688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23724

East Asian (EAS)

AF:

0.00

AC:

AN:

32200

South Asian (SAS)

AF:

0.00

AC:

AN:

76820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48646

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5470

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1070012

Other (OTH)

AF:

0.00

AC:

AN:

56574

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Uncertain

0.078

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.024

T;.;.;.;.;.

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.69

LIST_S2

Uncertain

0.88

D;D;D;D;D;D

M_CAP

Pathogenic

0.67

MetaRNN

Benign

0.29

T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.34

N;.;.;N;.;.

PhyloP100

3.9

PrimateAI

Pathogenic

0.96

PROVEAN

Benign

-0.11

.;N;.;N;.;.

REVEL

Benign

0.18

Sift

Benign

0.035

.;D;.;D;.;.

Sift4G

Benign

0.11

.;T;.;T;.;.

Polyphen

0.97

D;.;.;.;.;.

Vest4

0.38, 0.37

MutPred

0.29

Loss of phosphorylation at V5 (P = 0.0171);Loss of phosphorylation at V5 (P = 0.0171);Loss of phosphorylation at V5 (P = 0.0171);Loss of phosphorylation at V5 (P = 0.0171);Loss of phosphorylation at V5 (P = 0.0171);Loss of phosphorylation at V5 (P = 0.0171);

MVP

0.58

ClinPred

0.65

GERP RS

3.1

PromoterAI

-0.047

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.097

gMVP

0.44

Mutation Taster

=84/16

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

Computational scores

Splicing

Publications

Other links and lift over