Genetic Variant DIPK2B:p.Arg143Leu (chrX-45191821-C-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_176819.4(DIPK2B):c.428G>T(p.Arg143Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,210,636 control chromosomes in the GnomAD database, including 17 homozygotes. There are 391 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 3 hom., 43 hem., cov: 23)

Exomes 𝑓: 0.0011 ( 14 hom. 348 hem. )

Consequence

DIPK2B
NM_176819.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.646

Publications

1 publications found

Variant links:

Genes affected

DIPK2B (HGNC:25866): (divergent protein kinase domain 2B) Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

DIPK2B links:

ENSG00000229491 (HGNC:):

ENSG00000229491 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004731655).

BP6

Variant X-45191821-C-A is Benign according to our data. Variant chrX-45191821-C-A is described in ClinVar as Benign. ClinVar VariationId is 3033826.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00112 (1229/1098049) while in subpopulation AMR AF = 0.0307 (1081/35204). AF 95% confidence interval is 0.0292. There are 14 homozygotes in GnomAdExome4. There are 348 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_176819.4. 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
	DIPK2B	NM_176819.4	MANE Select	c.428G>T	p.Arg143Leu	missense	Exon 2 of 5	NP_789789.2
	DIPK2B	NM_024689.3		c.428G>T	p.Arg143Leu	missense	Exon 2 of 3	NP_078965.2	Q9H7Y0-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DIPK2B	ENST00000398000.7	TSL:5 MANE Select	c.428G>T	p.Arg143Leu	missense	Exon 2 of 5	ENSP00000381086.2	Q9H7Y0-1
DIPK2B	ENST00000377934.4	TSL:1	c.428G>T	p.Arg143Leu	missense	Exon 2 of 3	ENSP00000367168.4	Q9H7Y0-2
DIPK2B	ENST00000905163.1		c.428G>T	p.Arg143Leu	missense	Exon 2 of 5	ENSP00000575222.1

Frequencies

GnomAD3 genomes

AF:

0.00154

AC:

173

AN:

112534

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000388

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0136

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00140

Gnomad SAS

AF:

0.000735

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000563

Gnomad OTH

AF:

0.00395

GnomAD2 exomes

AF:

0.00493

AC:

903

AN:

183149

AF XY:

0.00349

show subpopulations

Gnomad AFR exome

AF:

0.000228

Gnomad AMR exome

AF:

0.0311

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00231

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000245

Gnomad OTH exome

AF:

0.00265

GnomAD4 exome

AF:

0.00112

AC:

1229

AN:

1098049

Hom.:

Cov.:

AF XY:

0.000958

AC XY:

348

AN XY:

363405

show subpopulations

African (AFR)

AF:

0.000417

AC:

AN:

26399

American (AMR)

AF:

0.0307

AC:

1081

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00182

AC:

AN:

30205

South Asian (SAS)

AF:

0.000148

AC:

AN:

54139

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40492

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.0000226

AC:

AN:

841996

Other (OTH)

AF:

0.00119

AC:

AN:

46095

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

120

180

240

300

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00155

AC:

174

AN:

112587

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

AN XY:

34743

show subpopulations

African (AFR)

AF:

0.000387

AC:

AN:

31010

American (AMR)

AF:

0.0136

AC:

146

AN:

10705

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2654

East Asian (EAS)

AF:

0.00140

AC:

AN:

3571

South Asian (SAS)

AF:

0.000737

AC:

AN:

2714

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6190

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0000563

AC:

AN:

53303

Other (OTH)

AF:

0.00390

AC:

AN:

1538

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000276

Hom.:

Bravo

AF:

0.00323

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.00330

AC:

401

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

DIPK2B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

0.99

FATHMM_MKL

Benign

0.38

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.0047

MetaSVM

Benign

-0.91

PhyloP100

0.65

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.13

Sift

Benign

0.077

Sift4G

Benign

0.16

Vest4

0.14

MVP

0.55

MPC

0.52

ClinPred

0.031

GERP RS

3.0

gMVP

0.68

Mutation Taster

=91/9

polymorphism (auto)

(source)

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over