rs3738573

Positions:

• chr1-84398573-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 13/19 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.30 (7129 hom., cov: 32)
  • Exomes 𝑓: 0.33 (82612 hom.)
• Consequence: DNASE2B NM_021233.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.874

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
DNASE2B	NM_021233.3	c.9G>C	p.Gln3His	missense_variant	1/6	ENST00000370665.4	NP_067056.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNASE2B	ENST00000370665.4	c.9G>C	p.Gln3His	missense_variant	1/6	1	NM_021233.3	ENSP00000359699.3

Frequencies

GnomAD3 genomes AF: 0.298 AC: 45299 AN: 151946 Hom.: 7124 Cov.: 32

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

GnomAD3 exomes AF: 0.312 AC: 77695 AN: 248900 Hom.: 12537 AF XY: 0.311 AC XY: 42034 AN XY: 135014

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 SAS exome AF: 0.257

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.: 35 AF XY: 0.331 AC XY: 240598 AN XY: 726878

Gnomad4 AFR exome AF: 0.193

Gnomad4 AMR exome AF: 0.273

Gnomad4 ASJ exome AF: 0.307

Gnomad4 EAS exome AF: 0.416

Gnomad4 SAS exome AF: 0.255

Gnomad4 FIN exome AF: 0.319

Gnomad4 NFE exome AF: 0.345

Gnomad4 OTH exome AF: 0.330

GnomAD4 genome AF: 0.298 AC: 45320 AN: 152064 Hom.: 7129 Cov.: 32 AF XY: 0.294 AC XY: 21834 AN XY: 74330

Gnomad4 AFR AF: 0.195

Gnomad4 AMR AF: 0.294

Gnomad4 ASJ AF: 0.298

Gnomad4 EAS AF: 0.411

Gnomad4 SAS AF: 0.265

Gnomad4 FIN AF: 0.306

Gnomad4 NFE AF: 0.353

Gnomad4 OTH AF: 0.317

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	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	11
DANN	Benign	0.55
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.059
Sift	Benign	0.21	T
Sift4G	Benign	0.29	T
Polyphen		0.61	P
Vest4		0.049
MutPred		0.063		Gain of catalytic residue at K4 (P = 0.0641);
MPC		0.071
ClinPred		0.014	T
GERP RS		3.0
Varity_R		0.048
gMVP		0.60

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3738573; hg19: chr1-84864256; COSMIC: COSV65743138; COSMIC: COSV65743138;