chr7-66639116-C-T

Variant names:

• chr7-66639116-C-T
• rs200652879
• NM_153033.5:c.754C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_153033.5(KCTD7):​c.754C>T​(p.Leu252Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L252V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCTD7 NM_153033.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.59
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-66639116-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 520953.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCTD7	NM_153033.5	c.754C>T	p.Leu252Phe	missense_variant	Exon 4 of 4	ENST00000639828.2	NP_694578.1
KCTD7	NM_001167961.2	c.754C>T	p.Leu252Phe	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.754C>T	p.Leu252Phe	missense_variant	Exon 4 of 4	2	NM_153033.5	ENSP00000492240.1
ENSG00000284461	ENST00000503687.2	n.397+187C>T		intron_variant	Intron 3 of 12	2		ENSP00000421074.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.078	T;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.61	D;D;D
MetaSVM	Uncertain	0.022	D
MutationAssessor	Benign	1.8	L;.;L
PhyloP100		5.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.1	.;.;N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0090	.;.;D
Sift4G	Uncertain	0.015	.;.;D
Polyphen		1.0	D;.;.
Vest4		0.85
MutPred		0.30		Gain of glycosylation at S253 (P = 0.146);Gain of glycosylation at S253 (P = 0.146);Gain of glycosylation at S253 (P = 0.146);
MVP		0.87
ClinPred		0.90	D
GERP RS		5.5
PromoterAI		-0.011	Neutral
Varity_R		0.36
gMVP		0.74
Mutation Taster		=33/67	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200652879; hg19: chr7-66104103; COSMIC: COSV106366972;