1-84414694-T-A

Variant names:

• chr1-84414694-T-A
• NM_021233.3:c.912T>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_021233.3(DNASE2B):​c.912T>A​(p.Asp304Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNASE2B NM_021233.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.912

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNASE2B	NM_021233.3	c.912T>A	p.Asp304Glu	missense_variant	Exon 6 of 6	ENST00000370665.4	NP_067056.2
DNASE2B	NM_058248.2	c.288T>A	p.Asp96Glu	missense_variant	Exon 4 of 4		NP_490649.1
DNASE2B	XM_047426625.1	c.675T>A	p.Asp225Glu	missense_variant	Exon 5 of 5		XP_047282581.1
DNASE2B	XM_011541878.3	c.288T>A	p.Asp96Glu	missense_variant	Exon 3 of 3		XP_011540180.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNASE2B	ENST00000370665.4	c.912T>A	p.Asp304Glu	missense_variant	Exon 6 of 6	1	NM_021233.3	ENSP00000359699.3
DNASE2B	ENST00000370662.3	c.288T>A	p.Asp96Glu	missense_variant	Exon 4 of 4	1		ENSP00000359696.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.912T>A (p.D304E) alteration is located in exon 6 (coding exon 6) of the DNASE2B gene. This alteration results from a T to A substitution at nucleotide position 912, causing the aspartic acid (D) at amino acid position 304 to be replaced by a glutamic acid (E). 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	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.073	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Pathogenic	3.6	H;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.94		Loss of ubiquitination at K307 (P = 0.0997);.;
MVP		0.72
MPC		0.42
ClinPred		1.0	D
GERP RS		0.41
Varity_R		0.95
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-84880377;