rs774026720

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_153033.5(KCTD7):c.335G>A(p.Arg112His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

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

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

KCTD7
NM_153033.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U: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 Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a domain BTB (size 98) in uniprot entity KCTD7_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_153033.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.976

PP5

Variant 7-66638273-G-A is Pathogenic according to our data. Variant chr7-66638273-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 206015.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCTD7	NM_153033.5 linkuse as main transcript	c.335G>A	p.Arg112His	missense_variant	3/4	ENST00000639828.2	NP_694578.1	Q96MP8-1A0A024RDN7
KCTD7	NM_001167961.2 linkuse as main transcript	c.335G>A	p.Arg112His	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.335G>A	p.Arg112His	missense_variant	3/4	2	NM_153033.5	ENSP00000492240.1		Q96MP8-1
ENSG00000284461	ENST00000503687.2 linkuse as main transcript	n.165G>A		non_coding_transcript_exon_variant	2/13	2		ENSP00000421074.1		E9PHB8

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152184

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:

0.00000398

AC:

AN:

251378

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727248

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74326

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:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Progressive myoclonic epilepsy type 3

Pathogenic:1Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with clinical features of epilepsy and neurodevelopmental disorders (PMID: 29655203). ClinVar contains an entry for this variant (Variation ID: 206015). This variant is present in population databases (rs774026720, ExAC 0.001%). This sequence change replaces arginine with histidine at codon 112 of the KCTD7 protein (p.Arg112His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 05, 2014

The R112H variant that is likely pathogenic has been identified in the KCTD7 gene. The R112H variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution alters a highly conserved position predicted to be within the BTB domain of the KCTD7 protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the R112H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in EPILEPSY panel(s). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

D;.;.;.;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D

MetaSVM

Uncertain

0.16

MutationAssessor

Pathogenic

3.5

H;.;.;H;.;.

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-4.9

.;D;.;D;.;.

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

.;D;.;D;.;.

Sift4G

Pathogenic

0.0

.;D;.;D;.;.

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.96

MutPred

0.89

Loss of methylation at R112 (P = 0.085);Loss of methylation at R112 (P = 0.085);Loss of methylation at R112 (P = 0.085);Loss of methylation at R112 (P = 0.085);Loss of methylation at R112 (P = 0.085);Loss of methylation at R112 (P = 0.085);

MVP

0.90

ClinPred

0.99

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.83

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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