rs2946642

Positions:

• chr15-65077193-G-T

Variant summary

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

The NM_001101362.3(KBTBD13):​c.378G>T​(p.Ala126=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 1,481,882 control chromosomes in the GnomAD database, including 123,433 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (16011 hom., cov: 34)
  • Exomes 𝑓: 0.40 (107422 hom.)
• Consequence: KBTBD13 NM_001101362.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.272

Genes affected

KBTBD13 (HGNC:37227): (kelch repeat and BTB domain containing 13) The gene belongs to a family of genes encoding proteins containing a BTB domain and several kelch repeats. The BTB domain functions as a protein-protein interaction module, which includes an ability to self-associate or to interact with non-BTB domain-containing proteins. The kelch motif typically occurs in groups of five to seven repeats, and has been found in proteins with diverse functions. Known functions of these family members include transcription regulation, ion channel tetramerization and gating, protein ubiquitination or degradation, and cytoskeleton regulation. The exact function of this family member has yet to be determined. [provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 15-65077193-G-T is Benign according to our data. Variant chr15-65077193-G-T is described in ClinVar as [Benign]. Clinvar id is 129309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-65077193-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.272 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.692 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KBTBD13	NM_001101362.3	c.378G>T	p.Ala126=	synonymous_variant	1/1	ENST00000432196.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KBTBD13	ENST00000432196.5	c.378G>T	p.Ala126=	synonymous_variant	1/1		NM_001101362.3	P1

Frequencies

GnomAD3 genomes AF: 0.449 AC: 68187 AN: 151734 Hom.: 15983 Cov.: 34

Gnomad AFR AF: 0.552

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.476

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.711

Gnomad SAS AF: 0.334

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.384

Gnomad OTH AF: 0.427

GnomAD3 exomes AF: 0.467 AC: 44457 AN: 95214 Hom.: 10771 AF XY: 0.449 AC XY: 23988 AN XY: 53418

Gnomad AFR exome AF: 0.634

Gnomad AMR exome AF: 0.573

Gnomad ASJ exome AF: 0.356

Gnomad EAS exome AF: 0.766

Gnomad SAS exome AF: 0.369

Gnomad FIN exome AF: 0.422

Gnomad NFE exome AF: 0.421

Gnomad OTH exome AF: 0.453

GnomAD4 exome AF: 0.397 AC: 527645 AN: 1330040 Hom.: 107422 Cov.: 52 AF XY: 0.395 AC XY: 257983 AN XY: 653144

Gnomad4 AFR exome AF: 0.563

Gnomad4 AMR exome AF: 0.550

Gnomad4 ASJ exome AF: 0.348

Gnomad4 EAS exome AF: 0.738

Gnomad4 SAS exome AF: 0.343

Gnomad4 FIN exome AF: 0.395

Gnomad4 NFE exome AF: 0.382

Gnomad4 OTH exome AF: 0.413

GnomAD4 genome AF: 0.450 AC: 68258 AN: 151842 Hom.: 16011 Cov.: 34 AF XY: 0.451 AC XY: 33453 AN XY: 74222

Gnomad4 AFR AF: 0.552

Gnomad4 AMR AF: 0.477

Gnomad4 ASJ AF: 0.325

Gnomad4 EAS AF: 0.711

Gnomad4 SAS AF: 0.333

Gnomad4 FIN AF: 0.403

Gnomad4 NFE AF: 0.384

Gnomad4 OTH AF: 0.431

Alfa AF: 0.407 Hom.: 2472

Bravo AF: 0.467

Asia WGS AF: 0.496 AC: 1697 AN: 3430

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 17, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2016	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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Nemaline myopathy 6 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Genome-Nilou Lab	Aug 19, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	8.2
DANN	Benign	0.79

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: rs2946642; hg19: chr15-65369531; COSMIC: COSV71351671; COSMIC: COSV71351671;