rs3754274

Variant names:

• chr1-84401927-G-A
• rs3754274
• NM_021233.3:c.152G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000370665.4(DNASE2B):​c.152G>A​(p.Arg51Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 1,530,442 control chromosomes in the GnomAD database, including 61,482 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 0.22 (4391 hom., cov: 32)
  • Exomes 𝑓: 0.28 (57091 hom.)
• Consequence: DNASE2B ENST00000370665.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.172
• Publications: 24 publications found

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

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

• BP4: Computational evidence support a benign effect (MetaRNN=5.4982305E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.363 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000370665.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNASE2B	NM_021233.3	MANE Select	c.152G>A	p.Arg51Lys	missense	Exon 2 of 6	NP_067056.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNASE2B	ENST00000370665.4	TSL:1 MANE Select	c.152G>A	p.Arg51Lys	missense	Exon 2 of 6	ENSP00000359699.3

Frequencies

GnomAD3 genomes AF: 0.223 AC: 33933 AN: 151950 Hom.: 4389 Cov.: 32

Gnomad AFR AF: 0.0789

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.377

Gnomad SAS AF: 0.235

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.236

GnomAD2 exomes AF: 0.252 AC: 38742 AN: 153456 AF XY: 0.253

Gnomad AFR exome AF: 0.0703

Gnomad AMR exome AF: 0.230

Gnomad ASJ exome AF: 0.206

Gnomad EAS exome AF: 0.364

Gnomad FIN exome AF: 0.228

Gnomad NFE exome AF: 0.285

Gnomad OTH exome AF: 0.242

GnomAD4 exome AF: 0.283 AC: 389838 AN: 1378374 Hom.: 57091 Cov.: 32 AF XY: 0.281 AC XY: 191084 AN XY: 681144

African (AFR) AF: 0.0672 AC: 1987 AN: 29566

American (AMR) AF: 0.234 AC: 5859 AN: 25038

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 4769 AN: 23262

East Asian (EAS) AF: 0.383 AC: 14092 AN: 36746

South Asian (SAS) AF: 0.220 AC: 16153 AN: 73286

European-Finnish (FIN) AF: 0.241 AC: 12305 AN: 51082

Middle Eastern (MID) AF: 0.156 AC: 873 AN: 5580

European-Non Finnish (NFE) AF: 0.296 AC: 318245 AN: 1076558

Other (OTH) AF: 0.272 AC: 15555 AN: 57256

GnomAD4 genome AF: 0.223 AC: 33935 AN: 152068 Hom.: 4391 Cov.: 32 AF XY: 0.220 AC XY: 16385 AN XY: 74342

African (AFR) AF: 0.0787 AC: 3264 AN: 41498

American (AMR) AF: 0.239 AC: 3657 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 711 AN: 3468

East Asian (EAS) AF: 0.377 AC: 1946 AN: 5158

South Asian (SAS) AF: 0.234 AC: 1125 AN: 4812

European-Finnish (FIN) AF: 0.221 AC: 2332 AN: 10558

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.295 AC: 20079 AN: 67984

Other (OTH) AF: 0.237 AC: 501 AN: 2116

Alfa AF: 0.258 Hom.: 11200

Bravo AF: 0.217

ESP6500AA AF: 0.0738 AC: 272

ESP6500EA AF: 0.281 AC: 2296

ExAC AF: 0.221 AC: 26162

Asia WGS AF: 0.324 AC: 1125 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.8
DANN	Benign	0.70
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.00055	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.17
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.058
Sift	Benign	0.49	T
Sift4G	Benign	0.30	T
Polyphen		0.0010	B
Vest4		0.027
MPC		0.076
ClinPred		0.00057	T
GERP RS		-0.37
Varity_R		0.076
gMVP		0.25
Mutation Taster		=99/1	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs3754274; hg19: chr1-84867610; COSMIC: COSV65743156; COSMIC: COSV65743156;