rs750033880

chr7-66633302-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_153033.5(KCTD7):c.172G>A(p.Gly58Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: KCTD7 NM_153033.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: 9.28

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain BTB (size 98) in uniprot entity KCTD7_HUMAN there are 16 pathogenic changes around while only 2 benign (89%) in NM_153033.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCTD7	NM_153033.5	c.172G>A	p.Gly58Arg	missense_variant	2/4	ENST00000639828.2
KCTD7	NM_001167961.2	c.172G>A	p.Gly58Arg	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCTD7	ENST00000639828.2	c.172G>A	p.Gly58Arg	missense_variant	2/4	2	NM_153033.5	A1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152098 Hom.: 0 Cov.: 31

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461644 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727126

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: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152098 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74306

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: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Progressive myoclonic epilepsy type 3 Pathogenic:1 Uncertain:1

Likely pathogenic, no assertion criteria provided	clinical testing	IRCCS Fondazione Stella Maris, University of Pisa	Aug 08, 2017	progressive epilepsy -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 09, 2022	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. ClinVar contains an entry for this variant (Variation ID: 469100). This missense change has been observed in individual(s) with clinical features of KCTD7-related conditions (PMID: 29302074, 30500434). This variant is present in population databases (rs750033880, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 58 of the KCTD7 protein (p.Gly58Arg). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Epilepsy, progressive myoclonic, 3, with intracellular inclusions Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D;.;.;.;.;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Pathogenic	3.9	H;.;.;H;.;.
MutationTaster	Benign	0.96	D
PrimateAI	Pathogenic	0.88	D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.94, 0.95
MutPred		0.94		Gain of methylation at G58 (P = 0.0541);Gain of methylation at G58 (P = 0.0541);Gain of methylation at G58 (P = 0.0541);Gain of methylation at G58 (P = 0.0541);Gain of methylation at G58 (P = 0.0541);Gain of methylation at G58 (P = 0.0541);
MVP		0.90
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.79
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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

Other links and lift over

dbSNP: rs750033880; hg19: chr7-66098289;