1-84408453-A-G

Variant names:

• chr1-84408453-A-G
• rs764865685
• ENST00000370662:c.-305A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_058248.2(DNASE2B):​c.-305A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000689 in 1,611,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: DNASE2B NM_058248.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.19

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.891

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNASE2B	NM_021233.3	c.320A>G	p.Tyr107Cys	missense_variant	Exon 3 of 6	ENST00000370665.4	NP_067056.2
DNASE2B	NM_058248.2	c.-305A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 4		NP_490649.1
DNASE2B	XM_047426625.1	c.83A>G	p.Tyr28Cys	missense_variant	Exon 2 of 5		XP_047282581.1
DNASE2B	NM_058248.2	c.-305A>G		5_prime_UTR_variant	Exon 1 of 4		NP_490649.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNASE2B	ENST00000370662	c.-305A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 4	1		ENSP00000359696.3
DNASE2B	ENST00000370665.4	c.320A>G	p.Tyr107Cys	missense_variant	Exon 3 of 6	1	NM_021233.3	ENSP00000359699.3
DNASE2B	ENST00000370662	c.-305A>G		5_prime_UTR_variant	Exon 1 of 4	1		ENSP00000359696.3

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000324 AC: 8 AN: 246768 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 133860

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000207

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000892

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000692 AC: 101 AN: 1458840 Hom.: 0 Cov.: 30 AF XY: 0.0000662 AC XY: 48 AN XY: 725598

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.000135

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000829

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74338

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000248 AC: 3

EpiCase AF: 0.0000548

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.320A>G (p.Y107C) alteration is located in exon 3 (coding exon 3) of the DNASE2B gene. This alteration results from a A to G substitution at nucleotide position 320, causing the tyrosine (Y) at amino acid position 107 to be replaced by a cysteine (C). 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	0.25
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.85	T
MutationAssessor	Pathogenic	3.2	M
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-8.1	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.67		Loss of phosphorylation at Y107 (P = 0.0398);
MVP		0.66
MPC		0.48
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.87
gMVP		0.77

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

LitVar

Other links and lift over

dbSNP: rs764865685; hg19: chr1-84874136;