chr15-65077892-A-G

Position:

• chr15-65077892-A-G

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.1077A>G​(p.Gly359Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00289 in 1,611,710 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0030 (10 hom.)
• Consequence: KBTBD13 NM_001101362.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.69

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=-0.64).
• BP6: Variant 15-65077892-A-G is Benign according to our data. Variant chr15-65077892-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 257450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.69 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00218 (331/152110) while in subpopulation NFE AF= 0.00394 (268/67954). AF 95% confidence interval is 0.00356. There are 2 homozygotes in gnomad4. There are 146 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 331 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KBTBD13	NM_001101362.3	c.1077A>G	p.Gly359Gly	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.1077A>G	p.Gly359Gly	synonymous_variant	1/1	6	NM_001101362.3	ENSP00000388723.2

Frequencies

GnomAD3 genomes AF: 0.00218 AC: 331 AN: 151992 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.000532

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.000578

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00142

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00394

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00211 AC: 511 AN: 242342 Hom.: 1 AF XY: 0.00217 AC XY: 289 AN XY: 132974

Gnomad AFR exome AF: 0.000351

Gnomad AMR exome AF: 0.000523

Gnomad ASJ exome AF: 0.000303

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00158

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.00351

Gnomad OTH exome AF: 0.00151

GnomAD4 exome AF: 0.00297 AC: 4329 AN: 1459600 Hom.: 10 Cov.: 84 AF XY: 0.00293 AC XY: 2125 AN XY: 726178

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.000881

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00150

Gnomad4 FIN exome AF: 0.00175

Gnomad4 NFE exome AF: 0.00350

Gnomad4 OTH exome AF: 0.00270

GnomAD4 genome AF: 0.00218 AC: 331 AN: 152110 Hom.: 2 Cov.: 34 AF XY: 0.00196 AC XY: 146 AN XY: 74364

Gnomad4 AFR AF: 0.000530

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.000578

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00142

Gnomad4 NFE AF: 0.00394

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00271 Hom.: 0

Bravo AF: 0.00207

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00349

EpiControl AF: 0.00255

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 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	Jun 06, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 01, 2020	- -

Nemaline myopathy 6 Benign:2

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

not provided Benign:2

Likely 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	Nov 01, 2024	KBTBD13: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	5.7
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs199526404; hg19: chr15-65370230;