7-66628949-C-T

Variant names:

• chr7-66628949-C-T
• rs551906037
• NM_153033.5:c.-116C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_153033.5(KCTD7):​c.-116C>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 0.00153 in 1,099,984 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (15 hom., cov: 30)
  • Exomes 𝑓: 0.00075 (7 hom.)
• Consequence: KCTD7 NM_153033.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.292
• Publications: 1 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 7-66628949-C-T is Benign according to our data. Variant chr7-66628949-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 676036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00639 (972/152152) while in subpopulation AFR AF = 0.0217 (901/41538). AF 95% confidence interval is 0.0205. There are 15 homozygotes in GnomAd4. There are 466 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCTD7	NM_153033.5	c.-116C>T		5_prime_UTR_variant	Exon 1 of 4	ENST00000639828.2	NP_694578.1
KCTD7	NM_001167961.2	c.-116C>T		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.-116C>T		5_prime_UTR_variant	Exon 1 of 4	2	NM_153033.5	ENSP00000492240.1
ENSG00000284461	ENST00000503687.2	n.-116C>T		upstream_gene_variant		2		ENSP00000421074.1

Frequencies

GnomAD3 genomes AF: 0.00639 AC: 971 AN: 152044 Hom.: 15 Cov.: 30

Gnomad AFR AF: 0.0217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00670

GnomAD4 exome AF: 0.000751 AC: 712 AN: 947832 Hom.: 7 Cov.: 12 AF XY: 0.000688 AC XY: 325 AN XY: 472402

African (AFR) AF: 0.0255 AC: 487 AN: 19088

American (AMR) AF: 0.00297 AC: 33 AN: 11128

Ashkenazi Jewish (ASJ) AF: 0.0000688 AC: 1 AN: 14544

East Asian (EAS) AF: 0.00 AC: 0 AN: 24282

South Asian (SAS) AF: 0.0000221 AC: 1 AN: 45282

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30538

Middle Eastern (MID) AF: 0.00209 AC: 6 AN: 2872

European-Non Finnish (NFE) AF: 0.000142 AC: 108 AN: 760036

Other (OTH) AF: 0.00190 AC: 76 AN: 40062

GnomAD4 genome AF: 0.00639 AC: 972 AN: 152152 Hom.: 15 Cov.: 30 AF XY: 0.00626 AC XY: 466 AN XY: 74388

African (AFR) AF: 0.0217 AC: 901 AN: 41538

American (AMR) AF: 0.00216 AC: 33 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67974

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.000210 Hom.: 0

Bravo AF: 0.00720

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Progressive myoclonic epilepsy type 3 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	6.4
DANN	Benign	0.91
PhyloP100		-0.29
PromoterAI		-0.090	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism

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: rs551906037; hg19: chr7-66093936;