16-2237066-T-C

Variant names:

• chr16-2237066-T-C
• NM_001374.3:c.173T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001374.3(DNASE1L2):​c.173T>C​(p.Val58Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,397,260 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: 0.0000021 (0 hom.)
• Consequence: DNASE1L2 NM_001374.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.20

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]

ENSG00000259780 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNASE1L2	NM_001374.3	c.173T>C	p.Val58Ala	missense_variant	Exon 3 of 7	ENST00000320700.10	NP_001365.1
DNASE1L2	NM_001301680.2	c.173T>C	p.Val58Ala	missense_variant	Exon 3 of 7		NP_001288609.1
DNASE1L2	XM_047433684.1	c.173T>C	p.Val58Ala	missense_variant	Exon 2 of 6		XP_047289640.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNASE1L2	ENST00000320700.10	c.173T>C	p.Val58Ala	missense_variant	Exon 3 of 7	1	NM_001374.3	ENSP00000316938.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1397260 Hom.: 0 Cov.: 31 AF XY: 0.00000290 AC XY: 2 AN XY: 689234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000278

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.173T>C (p.V58A) alteration is located in exon 3 (coding exon 2) of the DNASE1L2 gene. This alteration results from a T to C substitution at nucleotide position 173, causing the valine (V) at amino acid position 58 to be replaced by an alanine (A). 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	0.74
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.;D;D;.;D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.40	N
LIST_S2	Uncertain	0.94	.;D;.;D;.;D
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Pathogenic	3.0	M;M;M;M;M;.
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.4	D;.;D;D;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0020	D;.;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;.;.
Vest4		0.72
MutPred		0.74		Loss of stability (P = 0.0027);Loss of stability (P = 0.0027);Loss of stability (P = 0.0027);Loss of stability (P = 0.0027);Loss of stability (P = 0.0027);.;
MVP		0.31
MPC		0.89
ClinPred		0.99	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.68

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-2287067;