16-2237118-G-T

Variant names:

• chr16-2237118-G-T
• rs761694305
• NM_001374.3:c.225G>T

Variant summary

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

The NM_001374.3(DNASE1L2):​c.225G>T​(p.Gln75His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,397,634 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• 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: 1.29
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21579927).

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.225G>T	p.Gln75His	missense	Exon 3 of 7	NP_001365.1	Q92874-1
	DNASE1L2	NM_001301680.2		c.225G>T	p.Gln75His	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.225G>T	p.Gln75His	missense	Exon 3 of 7	ENSP00000316938.5	Q92874-1
	DNASE1L2	ENST00000564065.5	TSL:1	c.225G>T	p.Gln75His	missense	Exon 2 of 6	ENSP00000454562.1	Q92874-1
	DNASE1L2	ENST00000567494.5	TSL:1	c.225G>T	p.Gln75His	missense	Exon 3 of 7	ENSP00000455358.1	Q92874-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000681 AC: 1 AN: 146788 AF XY: 0.0000127

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000916

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1397634 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 689572

African (AFR) AF: 0.00 AC: 0 AN: 31716

American (AMR) AF: 0.00 AC: 0 AN: 35778

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25168

East Asian (EAS) AF: 0.0000278 AC: 1 AN: 35942

South Asian (SAS) AF: 0.00 AC: 0 AN: 79402

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47006

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5262

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1079370

Other (OTH) AF: 0.00 AC: 0 AN: 57990

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.025
Eigen_PC	Benign	-0.067
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.3
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.24
Sift	Benign	0.10	T
Sift4G	Benign	0.17	T
Polyphen		0.94	P
Vest4		0.14
MutPred		0.37		Gain of disorder (P = 0.165)
MVP		0.65
MPC		0.22
ClinPred		0.48	T
GERP RS		2.3
PromoterAI		-0.0094	Neutral
Varity_R		0.13
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs761694305; hg19: chr16-2287119;