16-2237111-T-C

Variant names:

• chr16-2237111-T-C
• rs2093513581
• NM_001374.3:c.218T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001374.3(DNASE1L2):​c.218T>C​(p.Met73Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000715 in 1,397,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M73K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: DNASE1L2 NM_001374.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.78
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4159366).

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>C	p.Met73Thr	missense	Exon 3 of 7	NP_001365.1	Q92874-1
	DNASE1L2	NM_001301680.2		c.218T>C	p.Met73Thr	missense	Exon 3 of 7	NP_001288609.1	Q92874-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNASE1L2	ENST00000320700.10	TSL:1 MANE Select	c.218T>C	p.Met73Thr	missense	Exon 3 of 7	ENSP00000316938.5	Q92874-1
	DNASE1L2	ENST00000564065.5	TSL:1	c.218T>C	p.Met73Thr	missense	Exon 2 of 6	ENSP00000454562.1	Q92874-1
	DNASE1L2	ENST00000567494.5	TSL:1	c.218T>C	p.Met73Thr	missense	Exon 3 of 7	ENSP00000455358.1	Q92874-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1397856 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 689678

African (AFR) AF: 0.00 AC: 0 AN: 31690

American (AMR) AF: 0.00 AC: 0 AN: 35802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25174

East Asian (EAS) AF: 0.00 AC: 0 AN: 35916

South Asian (SAS) AF: 0.00 AC: 0 AN: 79410

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5288

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1079412

Other (OTH) AF: 0.00 AC: 0 AN: 57994

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	-0.070
Eigen_PC	Benign	-0.039
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.8
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.15
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.28	B
Vest4		0.47
MutPred		0.55		Gain of disorder (P = 0.094)
MVP		0.40
MPC		0.52
ClinPred		1.0	D
GERP RS		3.2
PromoterAI		-0.0020	Neutral
Varity_R		0.81
gMVP		0.77

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: rs2093513581; hg19: chr16-2287112;