rs368781046

Positions:

• chr15-65077769-C-G
• chr15-65077769-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001101362.3(KBTBD13):​c.954C>G​(p.Thr318Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00346 in 1,580,356 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0034 (23 hom.)
• Consequence: KBTBD13 NM_001101362.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.73

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=-0.81).
• BP6: Variant 15-65077769-C-G is Benign according to our data. Variant chr15-65077769-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 129312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-65077769-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.73 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00395 (601/152342) while in subpopulation EAS AF= 0.0108 (56/5180). AF 95% confidence interval is 0.0087. There are 2 homozygotes in gnomad4. There are 328 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 601 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KBTBD13	NM_001101362.3	c.954C>G	p.Thr318Thr	synonymous_variant	1/1	ENST00000432196.5	NP_001094832.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KBTBD13	ENST00000432196.5	c.954C>G	p.Thr318Thr	synonymous_variant	1/1	6	NM_001101362.3	ENSP00000388723.2

Frequencies

GnomAD3 genomes AF: 0.00394 AC: 600 AN: 152226 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.0325

Gnomad EAS AF: 0.0106

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00309

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.00551 AC: 1013 AN: 183844 Hom.: 11 AF XY: 0.00525 AC XY: 540 AN XY: 102896

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00704

Gnomad ASJ exome AF: 0.0305

Gnomad EAS exome AF: 0.0102

Gnomad SAS exome AF: 0.00344

Gnomad FIN exome AF: 0.0000923

Gnomad NFE exome AF: 0.00319

Gnomad OTH exome AF: 0.00679

GnomAD4 exome AF: 0.00341 AC: 4874 AN: 1428014 Hom.: 23 Cov.: 83 AF XY: 0.00354 AC XY: 2508 AN XY: 708876

Gnomad4 AFR exome AF: 0.000609

Gnomad4 AMR exome AF: 0.00697

Gnomad4 ASJ exome AF: 0.0302

Gnomad4 EAS exome AF: 0.00836

Gnomad4 SAS exome AF: 0.00408

Gnomad4 FIN exome AF: 0.000170

Gnomad4 NFE exome AF: 0.00247

Gnomad4 OTH exome AF: 0.00619

GnomAD4 genome AF: 0.00395 AC: 601 AN: 152342 Hom.: 2 Cov.: 34 AF XY: 0.00440 AC XY: 328 AN XY: 74498

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00999

Gnomad4 ASJ AF: 0.0325

Gnomad4 EAS AF: 0.0108

Gnomad4 SAS AF: 0.00517

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00309

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.00449 Hom.: 1

Bravo AF: 0.00465

Asia WGS AF: 0.00376 AC: 13 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 20, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 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, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 30, 2016	- -

Nemaline myopathy 6 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	Jan 31, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	KBTBD13: BP4, BP7, BS2 -

KBTBD13-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 30, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.2
DANN	Benign	0.70

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: rs368781046; hg19: chr15-65370107;