7-66628996-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_153033.5(KCTD7):c.-69C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000312 in 1,438,066 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00031 (2 hom.)
• Consequence: KCTD7 NM_153033.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.252

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_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000306 (394/1286076) while in subpopulation MID AF= 0.00215 (9/4180). AF 95% confidence interval is 0.00112. There are 2 homozygotes in gnomad4_exome. There are 193 alleles in male gnomad4_exome subpopulation. Median coverage is 22. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCTD7	NM_153033.5	c.-69C>T		5_prime_UTR_variant	1/4	ENST00000639828.2
KCTD7	NM_001167961.2	c.-69C>T		5_prime_UTR_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCTD7	ENST00000639828.2	c.-69C>T		5_prime_UTR_variant	1/4	2	NM_153033.5	A1
KCTD7	ENST00000443322.1	c.-69C>T		5_prime_UTR_variant	1/5	1		P4
KCTD7	ENST00000275532.8	c.-69C>T		5_prime_UTR_variant	1/4	4
KCTD7	ENST00000640385.1	c.-69C>T		5_prime_UTR_variant	1/5	5

Frequencies

GnomAD3 genomes AF: 0.000356 AC: 54 AN: 151882 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000280

Gnomad OTH AF: 0.000958

GnomAD4 exome AF: 0.000306 AC: 394 AN: 1286076 Hom.: 2 Cov.: 22 AF XY: 0.000304 AC XY: 193 AN XY: 635866

Gnomad4 AFR exome AF: 0.000117

Gnomad4 AMR exome AF: 0.000340

Gnomad4 ASJ exome AF: 0.00596

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000167

Gnomad4 FIN exome AF: 0.0000236

Gnomad4 NFE exome AF: 0.000188

Gnomad4 OTH exome AF: 0.000685

GnomAD4 genome AF: 0.000355 AC: 54 AN: 151990 Hom.: 0 Cov.: 30 AF XY: 0.000390 AC XY: 29 AN XY: 74308

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000280

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000347 Hom.: 0

Bravo AF: 0.000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Progressive myoclonic epilepsy type 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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	-0.65
Cadd	Benign	16
Dann	Benign	0.90
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

Publications

LitVar

Other links and lift over

dbSNP: rs536230559; hg19: chr7-66093983;