rs796052686

Variant names:

• chr7-66638394-G-A
• rs796052686
• NM_153033.5:c.456G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-66638394-G-A
• chr7-66638394-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_153033.5(KCTD7):​c.456G>A​(p.Val152Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: KCTD7 NM_153033.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 0.190
• Publications: 2 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-66638394-G-A is Pathogenic according to our data. Variant chr7-66638394-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 206004.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCTD7	NM_153033.5	c.456G>A	p.Val152Val	synonymous_variant	Exon 3 of 4	ENST00000639828.2	NP_694578.1
KCTD7	NM_001167961.2	c.456G>A	p.Val152Val	synonymous_variant	Exon 3 of 5		NP_001161433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCTD7	ENST00000639828.2	c.456G>A	p.Val152Val	synonymous_variant	Exon 3 of 4	2	NM_153033.5	ENSP00000492240.1
ENSG00000284461	ENST00000503687.2	n.286G>A		non_coding_transcript_exon_variant	Exon 2 of 13	2		ENSP00000421074.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251394 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Progressive myoclonic epilepsy type 3 Pathogenic:2

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 152 of the KCTD7 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the KCTD7 protein. This variant is present in population databases (rs796052686, gnomAD 0.009%). This variant has been observed in individual(s) with clinical features of progressive myoclonic epilepsy (PMID: 31160820, 33970744; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 206004). Studies have shown that this variant alters KCTD7 gene expression (PMID: 31160820, 33970744). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Aug 22, 2017

Undiagnosed Diseases Network, NIH

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Heterozygous c.280C>T (p.R94W) likely pathogenic variant and c.456G>A (p.V152V) variant of unknown clinical significance in the KCTD7 gene were detected by exome sequencing and confirmed by Sanger sequencing this individual and her similarly affected younger brother. The c.280C>T (p.R94W) likely pathogenic variant has been previously reported in the homozygous state in two apparently unrelated Turkish patients [PMID 22693283, 22606975]. The potential pathogenicity of the variant is also supported by a recent functional study [PMID 27742667]. The c.456G>A (p.V152V) variant was predicted to affect splicing by in silico modeling. This effect on splicing was confirmed by RNA sequencing which showed evidence of a novel splice donor site that prematurely terminates exon 3 of KCTD7 in patient samples. Splicing effect was also confirmed by Sanger sequencing of amplified cDNA corresponding to KCTD7 exons 2-4 which showed two discrete bands in patients compared to one band in unrelated controls [Zastrow et al., ASHG 2017]. Whole exome sequencing analysis and Sanger analysis showed that the father is heterozygous for c.280C>T (p.R94W) and the mother is heterozygous for c.456G>A (p.V152V), indicating the two variants are in trans in this individual and her brother. -

not provided Uncertain:1

Aug 24, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant of uncertain significance has been identified in the KCTD7 gene. The c.456 G>A variant hasnot been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016). Several in silico splice prediction models predict that c.456 G>A strengthens a cryptic splice donor site which may supplant the natural donor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	14
DANN	Uncertain	1.0
PhyloP100		0.19
PromoterAI		0.067	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.33		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs796052686; hg19: chr7-66103381;