16-2237118-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001374.3(DNASE1L2):​c.225G>C​(p.Gln75His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 1,549,828 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

DNASE1L2
NM_001374.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.29
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.16664809).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DNASE1L2NM_001374.3 linkc.225G>C p.Gln75His missense_variant Exon 3 of 7 ENST00000320700.10 NP_001365.1 Q92874-1
DNASE1L2NM_001301680.2 linkc.225G>C p.Gln75His missense_variant Exon 3 of 7 NP_001288609.1 Q92874-1
DNASE1L2XM_047433684.1 linkc.225G>C p.Gln75His missense_variant Exon 2 of 6 XP_047289640.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DNASE1L2ENST00000320700.10 linkc.225G>C p.Gln75His missense_variant Exon 3 of 7 1 NM_001374.3 ENSP00000316938.5 Q92874-1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152192
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000886
AC:
13
AN:
146788
Hom.:
0
AF XY:
0.000102
AC XY:
8
AN XY:
78780
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000406
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000185
Gnomad OTH exome
AF:
0.000476
GnomAD4 exome
AF:
0.000107
AC:
149
AN:
1397636
Hom.:
0
Cov.:
31
AF XY:
0.000110
AC XY:
76
AN XY:
689574
show subpopulations
Gnomad4 AFR exome
AF:
0.0000631
Gnomad4 AMR exome
AF:
0.0000280
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:
0.000121
Gnomad4 OTH exome
AF:
0.000207
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152192
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74356
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000902
Hom.:
0
Bravo
AF:
0.0000756
ExAC
AF:
0.0000194
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 09, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.225G>C (p.Q75H) alteration is located in exon 3 (coding exon 2) of the DNASE1L2 gene. This alteration results from a G to C substitution at nucleotide position 225, causing the glutamine (Q) at amino acid position 75 to be replaced by a histidine (H). 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
Benign
0.17
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.29
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.36
T;.;T;T;.;T
Eigen
Benign
-0.025
Eigen_PC
Benign
-0.067
FATHMM_MKL
Benign
0.46
N
LIST_S2
Benign
0.57
.;T;.;T;.;T
M_CAP
Benign
0.053
D
MetaRNN
Benign
0.17
T;T;T;T;T;T
MetaSVM
Benign
-0.49
T
MutationAssessor
Benign
1.9
L;L;L;L;L;.
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-1.6
N;.;N;N;N;N
REVEL
Benign
0.24
Sift
Benign
0.10
T;.;T;T;T;T
Sift4G
Benign
0.17
T;T;T;T;T;T
Polyphen
0.94
P;.;P;P;.;.
Vest4
0.14
MutPred
0.37
Gain of disorder (P = 0.165);Gain of disorder (P = 0.165);Gain of disorder (P = 0.165);Gain of disorder (P = 0.165);Gain of disorder (P = 0.165);.;
MVP
0.65
MPC
0.22
ClinPred
0.35
T
GERP RS
2.3
Varity_R
0.13
gMVP
0.42

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs761694305; hg19: chr16-2287119; API