rs754476100

Positions:

• chr7-66633380-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_153033.5(KCTD7):​c.250C>T​(p.Arg84Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: KCTD7 NM_153033.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 4.52

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 7 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, 0.912
• PP5: Variant 7-66633380-C-T is Pathogenic according to our data. Variant chr7-66633380-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 469102.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCTD7	NM_153033.5	c.250C>T	p.Arg84Trp	missense_variant	2/4	ENST00000639828.2	NP_694578.1
KCTD7	NM_001167961.2	c.250C>T	p.Arg84Trp	missense_variant	2/5		NP_001161433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCTD7	ENST00000639828.2	c.250C>T	p.Arg84Trp	missense_variant	2/4	2	NM_153033.5	ENSP00000492240	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251448 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135894

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461804 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727216

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000896 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Progressive myoclonic epilepsy type 3 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 13, 2021	This sequence change replaces arginine with tryptophan at codon 84 of the KCTD7 protein (p.Arg84Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs754476100, ExAC 0.001%). This missense change has been observed in individual(s) with opsoclonus-myoclonus ataxia like syndrome (PMID: 22638565). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. 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. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Lab, NIMHANS, National Institute of Mental Health and Neuro Sciences	-	The missense variant NM_153033.5:c.250C>T; NP_694578.1:p.Arg84Trp causes a change at the same amino acid residue as a previously established pathogenic variant. The p.Arg84Trp variant is a previously reported ClinVar variant of uncertain significance Accession: VCV000469102.7. The p.Arg84Trp variant is novel (not in any individuals) in 1000 Genomes, as well as in our inhouse database . The p.Arg84Trp variant is observed in 1/33,582 (0.003%) alleles from individuals of gnomAD Latino background in gnomAD. There is a moderate physicochemical difference between arginine and tryptophan. The gene KCTD7 has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 1.26. The gene KCTD7 contains 15 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. The p.Arg84Trp missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 84 of KCTD7 is conserved in all mammalian species. The nucleotide c.250 in KCTD7 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. The variant was observed in a compound heterozygous state with another pathogenic variant (VCV001069708.6) in this individual. In addition, the patients phenotype matches with that of the disorder caused by pathogenic variants in KCTD7 gene. For these reasons, this variant has been classified as Likely Pathogenic (PM2 PP2 PP3 PM5 PM3 PP4_Moderate). -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 26, 2022

Variant summary: KCTD7 c.250C>T (p.Arg84Trp) results in a non-conservative amino acid change located in the Potassium channel tetramerisation-type BTB domain (IPR003131) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251448 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.250C>T has been reported in the literature in at least one compound heterozygous individual affected with Acute onset Myoclonus and Ataxia (Blumkin_2012). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter has assessed the variant since 2014 without evidence for independent evaluation: the variant was classified as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	D;.;.;.;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.9	H;.;.;H;.;.
MutationTaster	Benign	0.56	N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.9	.;D;.;D;.;.
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0060	.;D;.;D;.;.
Sift4G	Uncertain	0.0020	.;D;.;D;.;.
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.95, 0.96
MutPred		0.61		Loss of disorder (P = 0.0449);Loss of disorder (P = 0.0449);Loss of disorder (P = 0.0449);Loss of disorder (P = 0.0449);Loss of disorder (P = 0.0449);Loss of disorder (P = 0.0449);
MVP		0.97
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.81
gMVP		0.78

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: rs754476100; hg19: chr7-66098367; COSMIC: COSV104993010;