chr1-84412513-C-T

Variant names:

• chr1-84412513-C-T
• rs774651218
• NM_021233.3:c.712C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021233.3(DNASE2B):​c.712C>T​(p.Leu238Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,612,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DNASE2B NM_021233.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0620
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08976674).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021233.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNASE2B	NM_021233.3	MANE Select	c.712C>T	p.Leu238Phe	missense	Exon 5 of 6	NP_067056.2	Q8WZ79-1
	DNASE2B	NM_058248.2		c.88C>T	p.Leu30Phe	missense	Exon 3 of 4	NP_490649.1	Q8WZ79-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNASE2B	ENST00000370665.4	TSL:1 MANE Select	c.712C>T	p.Leu238Phe	missense	Exon 5 of 6	ENSP00000359699.3	Q8WZ79-1
	DNASE2B	ENST00000370662.3	TSL:1	c.88C>T	p.Leu30Phe	missense	Exon 3 of 4	ENSP00000359696.3	Q8WZ79-2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152132 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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249772 AF XY: 0.00

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460406 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726468

African (AFR) AF: 0.0000599 AC: 2 AN: 33378

American (AMR) AF: 0.00 AC: 0 AN: 44426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 85942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111424

Other (OTH) AF: 0.00 AC: 0 AN: 60344

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74290

African (AFR) AF: 0.0000966 AC: 4 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.062
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.019
Sift	Benign	0.24	T
Sift4G	Benign	0.22	T
Polyphen		0.025	B
Vest4		0.11
MutPred		0.47		Loss of ubiquitination at K236 (P = 0.0801)
MVP		0.12
MPC		0.097
ClinPred		0.057	T
GERP RS		2.8
Varity_R		0.082
gMVP		0.48
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs774651218; hg19: chr1-84878196;