rs3754274

Positions:

• chr1-84401927-G-A

Variant summary

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

The NM_021233.3(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. 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.22 (4391 hom., cov: 32)
  • Exomes 𝑓: 0.28 (57091 hom.)
• Consequence: DNASE2B NM_021233.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.172

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=5.4982305E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.363 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNASE2B	NM_021233.3	c.152G>A	p.Arg51Lys	missense_variant	2/6	ENST00000370665.4	NP_067056.2
DNASE2B	XM_047426625.1	c.-86G>A		5_prime_UTR_variant	1/5		XP_047282581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNASE2B	ENST00000370665.4	c.152G>A	p.Arg51Lys	missense_variant	2/6	1	NM_021233.3	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

GnomAD3 exomes AF: 0.252 AC: 38742 AN: 153456 Hom.: 5202 AF XY: 0.253 AC XY: 20818 AN XY: 82230

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 SAS exome AF: 0.220

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

Gnomad4 AFR exome AF: 0.0672

Gnomad4 AMR exome AF: 0.234

Gnomad4 ASJ exome AF: 0.205

Gnomad4 EAS exome AF: 0.383

Gnomad4 SAS exome AF: 0.220

Gnomad4 FIN exome AF: 0.241

Gnomad4 NFE exome AF: 0.296

Gnomad4 OTH exome AF: 0.272

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

Gnomad4 AFR AF: 0.0787

Gnomad4 AMR AF: 0.239

Gnomad4 ASJ AF: 0.205

Gnomad4 EAS AF: 0.377

Gnomad4 SAS AF: 0.234

Gnomad4 FIN AF: 0.221

Gnomad4 NFE AF: 0.295

Gnomad4 OTH AF: 0.237

Alfa AF: 0.271 Hom.: 9344

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 v4.3

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
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

Splicing

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

Publications

LitVar

Other links and lift over

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