rs146917406

chr15-65077609-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001101362.3(KBTBD13):c.794G>A(p.Gly265Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,582,006 control chromosomes in the GnomAD database, including 169 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G265S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0091 (11 hom., cov: 33)
  • Exomes 𝑓: 0.012 (158 hom.)
• Consequence: KBTBD13 NM_001101362.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 9.72

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 -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.015187234).
• BP6: Variant 15-65077609-G-A is Benign according to our data. Variant chr15-65077609-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 129310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-65077609-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00909 (1384/152288) while in subpopulation NFE AF= 0.0139 (943/67998). AF 95% confidence interval is 0.0131. There are 11 homozygotes in gnomad4. There are 713 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1384 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KBTBD13	NM_001101362.3	c.794G>A	p.Gly265Asp	missense_variant	1/1	ENST00000432196.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KBTBD13	ENST00000432196.5	c.794G>A	p.Gly265Asp	missense_variant	1/1		NM_001101362.3	P1

Frequencies

GnomAD3 genomes AF: 0.00910 AC: 1384 AN: 152170 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0250

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0139

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00820 AC: 1582 AN: 192922 Hom.: 21 AF XY: 0.00807 AC XY: 870 AN XY: 107828

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.00610

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00195

Gnomad FIN exome AF: 0.0206

Gnomad NFE exome AF: 0.0134

Gnomad OTH exome AF: 0.00749

GnomAD4 exome AF: 0.0125 AC: 17810 AN: 1429718 Hom.: 158 Cov.: 44 AF XY: 0.0121 AC XY: 8602 AN XY: 710168

Gnomad4 AFR exome AF: 0.00119

Gnomad4 AMR exome AF: 0.00260

Gnomad4 ASJ exome AF: 0.00590

Gnomad4 EAS exome AF: 0.0000261

Gnomad4 SAS exome AF: 0.00195

Gnomad4 FIN exome AF: 0.0193

Gnomad4 NFE exome AF: 0.0145

Gnomad4 OTH exome AF: 0.00992

GnomAD4 genome AF: 0.00909 AC: 1384 AN: 152288 Hom.: 11 Cov.: 33 AF XY: 0.00957 AC XY: 713 AN XY: 74480

Gnomad4 AFR AF: 0.00197

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.00606

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0250

Gnomad4 NFE AF: 0.0139

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.0114 Hom.: 4

Bravo AF: 0.00780

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.0125 AC: 48

ESP6500AA AF: 0.00199 AC: 7

ESP6500EA AF: 0.0130 AC: 101

ExAC AF: 0.00877 AC: 1021

Asia WGS AF: 0.000577 AC: 2 AN: 3478

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	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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 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	May 11, 2021	- -

Nemaline myopathy 6 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 03, 2022	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

KBTBD13: PP3, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.015	T
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	4.3	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MVP		0.80
MPC		1.7
ClinPred		0.054	T
GERP RS		5.3
Varity_R		0.96
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146917406; hg19: chr15-65369947; COSMIC: COSV71351352; COSMIC: COSV71351352;