13-41130768-G-A

Position:

• chr13-41130768-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4 BS2

The NM_152903.5(KBTBD6):​c.1744C>T​(p.Arg582Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: KBTBD6 NM_152903.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0100

Genes affected

KBTBD6 (HGNC:25340): (kelch repeat and BTB domain containing 6) Involved in proteasome-mediated ubiquitin-dependent protein catabolic process; protein K48-linked ubiquitination; and regulation of Rac protein signal transduction. Located in cytoplasm and nucleus. Part of Cul3-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33653447).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KBTBD6	NM_152903.5	c.1744C>T	p.Arg582Trp	missense_variant	1/1	ENST00000379485.2	NP_690867.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KBTBD6	ENST00000379485.2	c.1744C>T	p.Arg582Trp	missense_variant	1/1	6	NM_152903.5	ENSP00000368799.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 02, 2023

The c.1744C>T (p.R582W) alteration is located in exon 1 (coding exon 1) of the KBTBD6 gene. This alteration results from a C to T substitution at nucleotide position 1744, causing the arginine (R) at amino acid position 582 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	0.97	L
MutationTaster	Benign	0.59	D;D
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.37
MutPred		0.49		Loss of disorder (P = 0.0347);
MVP		0.46
MPC		2.1
ClinPred		0.95	D
GERP RS		1.6
Varity_R		0.19
gMVP		0.85

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: rs2030073629; hg19: chr13-41704904;