rs1346070646

Positions:

• chr7-66629078-C-G
• chr7-66629078-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_153033.5(KCTD7):​c.14C>G​(p.Thr5Arg) 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. Variant has been reported in ClinVar 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.91

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a chain BTB/POZ domain-containing protein KCTD7 (size 288) in uniprot entity KCTD7_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_153033.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2662717).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCTD7	NM_153033.5	c.14C>G	p.Thr5Arg	missense_variant	1/4	ENST00000639828.2	NP_694578.1
KCTD7	NM_001167961.2	c.14C>G	p.Thr5Arg	missense_variant	1/5		NP_001161433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCTD7	ENST00000639828.2	c.14C>G	p.Thr5Arg	missense_variant	1/4	2	NM_153033.5	ENSP00000492240	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1374938 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 679868

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Progressive myoclonic epilepsy type 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2021

This sequence change replaces threonine with arginine at codon 5 of the KCTD7 protein (p.Thr5Arg). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with KCTD7-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.026	T;.;.;.;.;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.81	T;T;T;T;T;T
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.27	T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.34	N;.;.;N;.;.
MutationTaster	Benign	0.99	N
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	-0.31	.;N;.;N;.;.
REVEL	Benign	0.23
Sift	Benign	0.065	.;T;.;T;.;.
Sift4G	Benign	0.20	.;T;.;T;.;.
Polyphen		0.39	B;.;.;.;.;.
Vest4		0.44, 0.38
MutPred		0.34		Gain of MoRF binding (P = 9e-04);Gain of MoRF binding (P = 9e-04);Gain of MoRF binding (P = 9e-04);Gain of MoRF binding (P = 9e-04);Gain of MoRF binding (P = 9e-04);Gain of MoRF binding (P = 9e-04);
MVP		0.51
ClinPred		0.60	D
GERP RS		3.1
Varity_R		0.36
gMVP		0.55

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

Other links and lift over

dbSNP: rs1346070646; hg19: chr7-66094065;