chr7-66628978-A-C

Variant names:

• chr7-66628978-A-C
• rs886062411
• NM_153033.5:c.-87A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_153033.5(KCTD7):​c.-87A>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000166 in 1,204,178 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: KCTD7 NM_153033.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.835
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCTD7	NM_153033.5	c.-87A>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 4	ENST00000639828.2	NP_694578.1
KCTD7	NM_153033.5	c.-87A>C		5_prime_UTR_variant	Exon 1 of 4	ENST00000639828.2	NP_694578.1
KCTD7	NM_001167961.2	c.-87A>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 5		NP_001161433.1
KCTD7	NM_001167961.2	c.-87A>C		5_prime_UTR_variant	Exon 1 of 5		NP_001161433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCTD7	ENST00000639828.2	c.-87A>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 4	2	NM_153033.5	ENSP00000492240.1
ENSG00000284461	ENST00000503687.2	n.-87A>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 13	2		ENSP00000421074.1
ENSG00000284461	ENST00000503687.2	n.-87A>C		non_coding_transcript_exon_variant	Exon 1 of 13	2		ENSP00000421074.1
KCTD7	ENST00000639828.2	c.-87A>C		5_prime_UTR_variant	Exon 1 of 4	2	NM_153033.5	ENSP00000492240.1
ENSG00000284461	ENST00000503687.2	n.-87A>C		5_prime_UTR_variant	Exon 1 of 13	2		ENSP00000421074.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000166 AC: 2 AN: 1204178 Hom.: 0 Cov.: 18 AF XY: 0.00000168 AC XY: 1 AN XY: 596132

African (AFR) AF: 0.00 AC: 0 AN: 24136

American (AMR) AF: 0.00 AC: 0 AN: 20310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20370

East Asian (EAS) AF: 0.00 AC: 0 AN: 25976

South Asian (SAS) AF: 0.00 AC: 0 AN: 64356

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38968

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3750

European-Non Finnish (NFE) AF: 0.00000209 AC: 2 AN: 957078

Other (OTH) AF: 0.00 AC: 0 AN: 49234

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Progressive myoclonic epilepsy type 3 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	20
DANN	Benign	0.72
PhyloP100		0.83
PromoterAI		-0.37	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs886062411; hg19: chr7-66093965;