Genetic Variant DNASE1L2:p.Met73Lys (chr16-2237111-T-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001374.3(DNASE1L2):c.218T>A(p.Met73Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000129 in 1,397,856 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

DNASE1L2
NM_001374.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.78

Publications

0 publications found

Variant links:

Genes affected

DNASE1L2 (HGNC:2958): (deoxyribonuclease 1 like 2) Predicted to enable DNA binding activity and deoxyribonuclease I activity. Predicted to be involved in DNA catabolic process, endonucleolytic. Predicted to act upstream of or within corneocyte development and hair follicle development. Predicted to be located in cytoplasm and extracellular region. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

DNASE1L2 links:

ENSG00000259780 (HGNC:):

ENSG00000259780 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374.3. 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
	DNASE1L2	NM_001374.3	MANE Select	c.218T>A	p.Met73Lys	missense	Exon 3 of 7	NP_001365.1	Q92874-1
	DNASE1L2	NM_001301680.2		c.218T>A	p.Met73Lys	missense	Exon 3 of 7	NP_001288609.1	Q92874-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNASE1L2	ENST00000320700.10	TSL:1 MANE Select	c.218T>A	p.Met73Lys	missense	Exon 3 of 7	ENSP00000316938.5	Q92874-1
DNASE1L2	ENST00000564065.5	TSL:1	c.218T>A	p.Met73Lys	missense	Exon 2 of 6	ENSP00000454562.1	Q92874-1
DNASE1L2	ENST00000567494.5	TSL:1	c.218T>A	p.Met73Lys	missense	Exon 3 of 7	ENSP00000455358.1	Q92874-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000129

AC:

AN:

1397856

Hom.:

Cov.:

AF XY:

0.0000145

AC XY:

AN XY:

689678

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31690

American (AMR)

AF:

0.00

AC:

AN:

35802

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25174

East Asian (EAS)

AF:

0.00

AC:

AN:

35916

South Asian (SAS)

AF:

0.00

AC:

AN:

79410

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47170

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5288

European-Non Finnish (NFE)

AF:

0.0000157

AC:

AN:

1079412

Other (OTH)

AF:

0.0000172

AC:

AN:

57994

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000313

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.037

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.66

Eigen

Benign

-0.049

Eigen_PC

Benign

-0.021

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.62

M_CAP

Benign

0.029

MetaRNN

Uncertain

0.55

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

PhyloP100

4.8

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-4.8

REVEL

Benign

0.14

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.49

Vest4

0.57

MutPred

0.68

Gain of disorder (P = 0.0165)

MVP

0.44

MPC

0.36

ClinPred

1.0

GERP RS

3.2

PromoterAI

0.00010

Neutral

(source)

Varity_R

0.96

gMVP

0.92

Mutation Taster

=74/26

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over