7-66639016-C-T

Position:

• chr7-66639016-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_153033.5(KCTD7):​c.654C>T​(p.Asp218Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,614,114 control chromosomes in the GnomAD database, including 497 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (61 hom., cov: 32)
  • Exomes 𝑓: 0.010 (436 hom.)
• Consequence: KCTD7 NM_153033.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.357

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]

ENSG00000284461 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016175508).
• BP6: Variant 7-66639016-C-T is Benign according to our data. Variant chr7-66639016-C-T is described in ClinVar as [Benign]. Clinvar id is 129371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-66639016-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.357 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0859 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCTD7	NM_153033.5	c.654C>T	p.Asp218Asp	synonymous_variant	4/4	ENST00000639828.2	NP_694578.1
KCTD7	NM_001167961.2	c.654C>T	p.Asp218Asp	synonymous_variant	4/5		NP_001161433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCTD7	ENST00000639828.2	c.654C>T	p.Asp218Asp	synonymous_variant	4/4	2	NM_153033.5	ENSP00000492240.1
ENSG00000284461	ENST00000503687.2	n.397+87C>T		intron_variant		2		ENSP00000421074.1

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2214 AN: 152112 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.00321

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0231

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.0927

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.0752

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00507

Gnomad OTH AF: 0.0192

GnomAD3 exomes AF: 0.0218 AC: 5491 AN: 251440 Hom.: 143 AF XY: 0.0201 AC XY: 2734 AN XY: 135900

Gnomad AFR exome AF: 0.00301

Gnomad AMR exome AF: 0.0384

Gnomad ASJ exome AF: 0.00347

Gnomad EAS exome AF: 0.0868

Gnomad SAS exome AF: 0.00862

Gnomad FIN exome AF: 0.0675

Gnomad NFE exome AF: 0.00541

Gnomad OTH exome AF: 0.0230

GnomAD4 exome AF: 0.0103 AC: 15019 AN: 1461884 Hom.: 436 Cov.: 32 AF XY: 0.0101 AC XY: 7331 AN XY: 727238

Gnomad4 AFR exome AF: 0.00427

Gnomad4 AMR exome AF: 0.0362

Gnomad4 ASJ exome AF: 0.00344

Gnomad4 EAS exome AF: 0.103

Gnomad4 SAS exome AF: 0.00929

Gnomad4 FIN exome AF: 0.0691

Gnomad4 NFE exome AF: 0.00322

Gnomad4 OTH exome AF: 0.0157

GnomAD4 genome AF: 0.0146 AC: 2227 AN: 152230 Hom.: 61 Cov.: 32 AF XY: 0.0178 AC XY: 1323 AN XY: 74410

Gnomad4 AFR AF: 0.00325

Gnomad4 AMR AF: 0.0233

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.0928

Gnomad4 SAS AF: 0.0110

Gnomad4 FIN AF: 0.0752

Gnomad4 NFE AF: 0.00507

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.00586 Hom.: 1

Bravo AF: 0.0106

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.0202 AC: 2456

Asia WGS AF: 0.0720 AC: 248 AN: 3478

EpiCase AF: 0.00338

EpiControl AF: 0.00338

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Progressive myoclonic epilepsy type 3 Benign:2

Benign, 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 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 26, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 25, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	2.9
DANN	Benign	0.67
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.30	T
MetaRNN	Benign	0.0016	T
GERP RS		-2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs117194263; hg19: chr7-66104003;