Genetic Variant NM_001101362.3:c.122G>C (chr15-65076937-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001101362.3(KBTBD13):c.122G>C(p.Arg41Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000712 in 1,404,392 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R41W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

KBTBD13
NM_001101362.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.865

Publications

1 publications found

Variant links:

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]

KBTBD13 links:

RASL12 (HGNC:30289): (RAS like family 12) Predicted to enable GDP binding activity; GTP binding activity; and GTPase activity. Predicted to be involved in signal transduction. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

RASL12 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KBTBD13	NM_001101362.3 link	c.122G>C	p.Arg41Pro	missense_variant	Exon 1 of 1	ENST00000432196.5	NP_001094832.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KBTBD13	ENST00000432196.5 link	c.122G>C	p.Arg41Pro	missense_variant	Exon 1 of 1	6	NM_001101362.3	ENSP00000388723.2
RASL12	ENST00000434605.2 link	c.-339C>G		upstream_gene_variant		2		ENSP00000412787.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.12e-7

AC:

AN:

1404392

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

695408

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32432

American (AMR)

AF:

0.00

AC:

AN:

38986

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25416

East Asian (EAS)

AF:

0.00

AC:

AN:

37126

South Asian (SAS)

AF:

0.00

AC:

AN:

80454

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36244

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4378

European-Non Finnish (NFE)

AF:

9.17e-7

AC:

AN:

1090842

Other (OTH)

AF:

0.00

AC:

AN:

58514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.081

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.63

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.75

M_CAP

Uncertain

0.29

MetaRNN

Uncertain

0.69

MetaSVM

Benign

-0.45

MutationAssessor

Uncertain

2.1

PhyloP100

0.86

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-4.9

REVEL

Uncertain

0.40

Sift

Uncertain

0.016

Sift4G

Benign

0.083

Vest4

0.54

ClinPred

0.98

GERP RS

3.6

PromoterAI

0.026

Neutral

(source)

Varity_R

0.83

gMVP

0.66

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over