rs1554397798

Variant names:

• chr7-66633368-A-G
• rs1554397798
• NM_153033.5:c.238A>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_153033.5(KCTD7):​c.238A>G​(p.Met80Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KCTD7 NM_153033.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.65

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]

ENSG00000284461 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 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, 0.824

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCTD7	NM_153033.5	c.238A>G	p.Met80Val	missense_variant	Exon 2 of 4	ENST00000639828.2	NP_694578.1
KCTD7	NM_001167961.2	c.238A>G	p.Met80Val	missense_variant	Exon 2 of 5		NP_001161433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCTD7	ENST00000639828.2	c.238A>G	p.Met80Val	missense_variant	Exon 2 of 4	2	NM_153033.5	ENSP00000492240.1
ENSG00000284461	ENST00000503687.2	n.144+4160A>G		intron_variant	Intron 1 of 12	2		ENSP00000421074.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Progressive myoclonic epilepsy type 3 Uncertain:1

Jun 24, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a KCTD7-related disease. This sequence change replaces methionine with valine at codon 80 of the KCTD7 protein (p.Met80Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D;.;.;.;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.9	M;.;.;M;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.3	.;D;.;D;.;.
REVEL	Uncertain	0.55
Sift	Uncertain	0.0050	.;D;.;D;.;.
Sift4G	Uncertain	0.011	.;D;.;D;.;.
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.90
MutPred		0.68		Gain of catalytic residue at M80 (P = 0.0484);Gain of catalytic residue at M80 (P = 0.0484);Gain of catalytic residue at M80 (P = 0.0484);Gain of catalytic residue at M80 (P = 0.0484);Gain of catalytic residue at M80 (P = 0.0484);Gain of catalytic residue at M80 (P = 0.0484);
MVP		0.61
ClinPred		0.97	D
GERP RS		4.8
Varity_R		0.77
gMVP		0.90

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: rs1554397798; hg19: chr7-66098355;