rs763830869

Variant names:

• chr7-66639152-A-C
• rs763830869
• NM_153033.5:c.790A>C

Your query was ambiguous. Multiple possible variants found:

• chr7-66639152-A-C
• chr7-66639152-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_153033.5(KCTD7):​c.790A>C​(p.Ile264Leu) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. I264I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCTD7 NM_153033.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.62
• Publications: 0 publications found

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

ENSG00000284461 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35352984).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCTD7	NM_153033.5	c.790A>C	p.Ile264Leu	missense_variant	Exon 4 of 4	ENST00000639828.2	NP_694578.1
KCTD7	NM_001167961.2	c.790A>C	p.Ile264Leu	missense_variant	Exon 4 of 5		NP_001161433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCTD7	ENST00000639828.2	c.790A>C	p.Ile264Leu	missense_variant	Exon 4 of 4	2	NM_153033.5	ENSP00000492240.1
ENSG00000284461	ENST00000503687.2	n.397+223A>C		intron_variant	Intron 3 of 12	2		ENSP00000421074.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Apr 16, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine with leucine at codon 264 of the KCTD7 protein (p.Ile264Leu). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and leucine. 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. 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: "Benign"; Align-GVGD: "Class C0"). 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	Uncertain	0.55
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.042	T;.;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.6	L;.;L;.
PhyloP100		8.6
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.16	.;.;N;.
REVEL	Benign	0.22
Sift	Benign	0.66	.;.;T;.
Sift4G	Benign	0.71	.;.;T;.
Polyphen		0.90	P;.;.;.
Vest4		0.57
MutPred		0.40		Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);.;
MVP		0.78
ClinPred		0.78	D
GERP RS		5.5
PromoterAI		-0.0045	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.39
Mutation Taster		=55/45	polymorphism

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

Other links and lift over

dbSNP: rs763830869; hg19: chr7-66104139;