Genetic Variant DNASE2B:p.Gln3His (chr1-84398573-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_021233.3(DNASE2B):c.9G>C(p.Gln3His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.33 in 1,613,260 control chromosomes in the GnomAD database, including 89,741 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.30 ( 7129 hom., cov: 32)

Exomes 𝑓: 0.33 ( 82612 hom. )

Consequence

DNASE2B
NM_021233.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.874

Publications

30 publications found

Variant links:

Genes affected

DNASE2B (HGNC:28875): (deoxyribonuclease 2 beta) The protein encoded by this gene shares considerable sequence similarity to, and is structurally related to DNase II. The latter is a well characterized endonuclease that catalyzes DNA hydrolysis in the absence of divalent cations at acidic pH. Unlike DNase II which is ubiquitously expressed, expression of this gene product is restricted to the salivary gland and lungs. The gene has been localized to chromosome 1p22.3 adjacent (and in opposite orientation) to the uricase pseudogene. Two transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

DNASE2B links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003954619).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.396 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNASE2B	NM_021233.3 link	c.9G>C	p.Gln3His	missense_variant	Exon 1 of 6	ENST00000370665.4	NP_067056.2	Q8WZ79-1Q66K39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNASE2B	ENST00000370665.4 link	c.9G>C	p.Gln3His	missense_variant	Exon 1 of 6	1	NM_021233.3	ENSP00000359699.3		Q8WZ79-1

Frequencies

GnomAD3 genomes

AF:

0.298

AC:

45299

AN:

151946

Hom.:

7124

Cov.:

show subpopulations

Gnomad AFR

AF:

0.195

Gnomad AMI

AF:

0.349

Gnomad AMR

AF:

0.294

Gnomad ASJ

AF:

0.298

Gnomad EAS

AF:

0.411

Gnomad SAS

AF:

0.267

Gnomad FIN

AF:

0.306

Gnomad MID

AF:

0.291

Gnomad NFE

AF:

0.353

Gnomad OTH

AF:

0.315

GnomAD2 exomes

AF:

0.312

AC:

77695

AN:

248900

AF XY:

0.311

show subpopulations

Gnomad AFR exome

AF:

0.193

Gnomad AMR exome

AF:

0.270

Gnomad ASJ exome

AF:

0.310

Gnomad EAS exome

AF:

0.405

Gnomad FIN exome

AF:

0.309

Gnomad NFE exome

AF:

0.342

Gnomad OTH exome

AF:

0.317

GnomAD4 exome

AF:

0.333

AC:

487092

AN:

1461196

Hom.:

82612

Cov.:

AF XY:

0.331

AC XY:

240598

AN XY:

726878

show subpopulations

African (AFR)

AF:

0.193

AC:

6458

AN:

33470

American (AMR)

AF:

0.273

AC:

12214

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.307

AC:

8021

AN:

26128

East Asian (EAS)

AF:

0.416

AC:

16529

AN:

39692

South Asian (SAS)

AF:

0.255

AC:

22001

AN:

86172

European-Finnish (FIN)

AF:

0.319

AC:

17048

AN:

53374

Middle Eastern (MID)

AF:

0.259

AC:

1494

AN:

5760

European-Non Finnish (NFE)

AF:

0.345

AC:

383388

AN:

1111546

Other (OTH)

AF:

0.330

AC:

19939

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

16887

33773

50660

67546

84433

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12170

24340

36510

48680

60850

<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:

0.298

AC:

45320

AN:

152064

Hom.:

7129

Cov.:

AF XY:

0.294

AC XY:

21834

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.195

AC:

8089

AN:

41494

American (AMR)

AF:

0.294

AC:

4498

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.298

AC:

1034

AN:

3472

East Asian (EAS)

AF:

0.411

AC:

2118

AN:

5154

South Asian (SAS)

AF:

0.265

AC:

1280

AN:

4824

European-Finnish (FIN)

AF:

0.306

AC:

3229

AN:

10566

Middle Eastern (MID)

AF:

0.289

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.353

AC:

24002

AN:

67950

Other (OTH)

AF:

0.317

AC:

667

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1613

3226

4839

6452

8065

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

460

920

1380

1840

2300

<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:

0.342

Hom.:

7023

Bravo

AF:

0.291

ESP6500AA

AF:

0.188

AC:

778

ESP6500EA

AF:

0.343

AC:

2894

ExAC

AF:

0.311

AC:

37611

Asia WGS

AF:

0.372

AC:

1295

AN:

3478

EpiCase

AF:

0.338

EpiControl

AF:

0.339

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.74

CADD

Benign

(source)

DANN

Benign

0.55

DEOGEN2

Benign

0.017

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.36

MetaRNN

Benign

0.0040

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.0

PhyloP100

0.87

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.21

REVEL

Benign

0.059

Sift

Benign

0.21

Sift4G

Benign

0.29

Polyphen

0.61

Vest4

0.049

MutPred

0.063

Gain of catalytic residue at K4 (P = 0.0641);

MPC

0.071

ClinPred

0.014

GERP RS

3.0

PromoterAI

-0.027

Neutral

(source)

Varity_R

0.048

gMVP

0.60

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over