Genetic Variant KRABD2:p.Val266Leu (chr17-8369571-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001304947.3(KRABD2):c.796G>C(p.Val266Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 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. V266I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

KRABD2
NM_001304947.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.141

Publications

0 publications found

Variant links:

Genes affected

KRABD2 (HGNC:26989): (KRAB-A domain containing 2) Predicted to enable nucleic acid binding activity. Predicted to be involved in DNA integration and regulation of transcription, DNA-templated. [provided by Alliance of Genome Resources, Apr 2022]

KRABD2 links:

ENSG00000263809 (HGNC:):

ENSG00000263809 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3762305).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001304947.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRABD2	NM_001304947.3	MANE Select	c.796G>C	p.Val266Leu	missense	Exon 2 of 2	NP_001291876.1	A8MX02
	KRABD2	NM_213597.3		c.1042G>C	p.Val348Leu	missense	Exon 2 of 2	NP_998762.1	Q6ZNG9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KRBA2	ENST00000396267.3	TSL:2 MANE Select	c.796G>C	p.Val266Leu	missense	Exon 2 of 2	ENSP00000379565.3	A8MX02
ENSG00000263809	ENST00000582471.1	TSL:5	n.*1779G>C		non_coding_transcript_exon	Exon 6 of 6	ENSP00000463847.1	J3QQQ9
ENSG00000263809	ENST00000582471.1	TSL:5	n.*1779G>C		3_prime_UTR	Exon 6 of 6	ENSP00000463847.1	J3QQQ9

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

9.9

(source)

DANN

Benign

0.53

DEOGEN2

Benign

0.056

Eigen

Benign

-0.98

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.066

LIST_S2

Benign

0.84

M_CAP

Benign

0.0029

MetaRNN

Benign

0.38

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

0.14

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-2.3

REVEL

Benign

0.10

Sift

Benign

0.061

Sift4G

Benign

0.31

Polyphen

0.014

Vest4

0.086

MutPred

0.80

Loss of methylation at K351 (P = 0.0901)

MVP

0.18

MPC

0.16

ClinPred

0.051

GERP RS

0.94

Varity_R

0.089

gMVP

0.18

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over