16-2237524-C-G

Variant names:

• chr16-2237524-C-G
• rs753517918
• NM_001374.3:c.466C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001374.3(DNASE1L2):​c.466C>G​(p.Pro156Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000415 in 1,446,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DNASE1L2 NM_001374.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.30

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054790318).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNASE1L2	NM_001374.3	c.466C>G	p.Pro156Ala	missense_variant	Exon 5 of 7	ENST00000320700.10	NP_001365.1
DNASE1L2	NM_001301680.2	c.466C>G	p.Pro156Ala	missense_variant	Exon 5 of 7		NP_001288609.1
DNASE1L2	XM_047433684.1	c.466C>G	p.Pro156Ala	missense_variant	Exon 4 of 6		XP_047289640.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNASE1L2	ENST00000320700.10	c.466C>G	p.Pro156Ala	missense_variant	Exon 5 of 7	1	NM_001374.3	ENSP00000316938.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000460 AC: 1 AN: 217256 Hom.: 0 AF XY: 0.00000837 AC XY: 1 AN XY: 119460

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000357

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000415 AC: 6 AN: 1446282 Hom.: 0 Cov.: 58 AF XY: 0.00000835 AC XY: 6 AN XY: 718180

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: 0.0000713

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000839 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.25
DANN	Benign	0.40
DEOGEN2	Benign	0.22	T;T;T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.35	.;.;T;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.055	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N;N;N;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.50	N;N;N;N
REVEL	Benign	0.0070
Sift	Benign	0.26	T;T;T;T
Sift4G	Benign	0.33	T;T;T;T
Polyphen		0.0010	B;B;B;.
Vest4		0.12
MutPred		0.34		Loss of glycosylation at P156 (P = 0.0031);Loss of glycosylation at P156 (P = 0.0031);Loss of glycosylation at P156 (P = 0.0031);.;
MVP		0.061
MPC		0.21
ClinPred		0.045	T
GERP RS		-1.8
Varity_R		0.029
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs753517918; hg19: chr16-2287525;