1-84414591-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021233.3(DNASE2B):c.809G>A(p.Arg270Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000176 in 1,613,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: DNASE2B NM_021233.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.01644665).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNASE2B	NM_021233.3	c.809G>A	p.Arg270Gln	missense_variant	6/6	ENST00000370665.4
DNASE2B	NM_058248.2	c.185G>A	p.Arg62Gln	missense_variant	4/4
DNASE2B	XM_047426625.1	c.572G>A	p.Arg191Gln	missense_variant	5/5
DNASE2B	XM_011541878.3	c.185G>A	p.Arg62Gln	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNASE2B	ENST00000370665.4	c.809G>A	p.Arg270Gln	missense_variant	6/6	1	NM_021233.3	P1
DNASE2B	ENST00000370662.3	c.185G>A	p.Arg62Gln	missense_variant	4/4	1

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000311 AC: 78 AN: 251086 Hom.: 0 AF XY: 0.000309 AC XY: 42 AN XY: 135704

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00213

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000162 AC: 237 AN: 1461794 Hom.: 0 Cov.: 30 AF XY: 0.000160 AC XY: 116 AN XY: 727188

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00185

Gnomad4 NFE exome AF: 0.000106

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.000404 AC XY: 30 AN XY: 74298

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000314 Hom.: 0

Bravo AF: 0.0000907

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000338 AC: 41

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 19, 2021

The c.809G>A (p.R270Q) alteration is located in exon 6 (coding exon 6) of the DNASE2B gene. This alteration results from a G to A substitution at nucleotide position 809, causing the arginine (R) at amino acid position 270 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.59
Cadd	Uncertain	23
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.041	T;.
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.016	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.13
Sift	Benign	0.045	D;D
Sift4G	Benign	0.15	T;T
Polyphen		1.0	D;.
Vest4		0.090
MVP		0.64
MPC		0.11
ClinPred		0.028	T
GERP RS		2.7
Varity_R		0.24
gMVP		0.43

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

LitVar

Other links and lift over

dbSNP: rs375823079; hg19: chr1-84880274; COSMIC: COSV65737831;