9-1051735-C-G

Position:

• chr9-1051735-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_181872.6(DMRT2):​c.122C>G​(p.Pro41Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DMRT2 NM_181872.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.78

Genes affected

DMRT2 (HGNC:2935): (doublesex and mab-3 related transcription factor 2) The protein encoded by this gene belongs to the DMRT gene family, sharing a DM DNA-binding domain with Drosophila 'doublesex' (dsx) and C. elegans mab3, genes involved in sex determination in these organisms. Also, this gene is located in a region of the human genome (chromosome 9p24.3) associated with gonadal dysgenesis and XY sex reversal. Hence this gene is one of the candidates for sex-determining gene(s) on chr 9. [provided by RefSeq, Apr 2010]

DMRT2 (HGNC:):

ACMG classification

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=0.12720838).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMRT2	NM_181872.6	c.122C>G	p.Pro41Arg	missense_variant	2/4	ENST00000358146.7	NP_870987.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMRT2	ENST00000358146.7	c.122C>G	p.Pro41Arg	missense_variant	2/4	1	NM_181872.6	ENSP00000350865.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1382092 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 682582

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 18, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with DMRT2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces proline with arginine at codon 41 of the DMRT2 protein (p.Pro41Arg). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Benign	0.052	.;.;T;.;T;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.41	.;.;T;.;.;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.13	T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.0	M;M;M;M;M;M
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.43	.;N;N;N;N;N
REVEL	Benign	0.032
Sift	Uncertain	0.0010	.;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D
Polyphen		0.20	.;.;B;.;B;.
Vest4		0.19
MutPred		0.17		Loss of glycosylation at P40 (P = 0.0777);Loss of glycosylation at P40 (P = 0.0777);Loss of glycosylation at P40 (P = 0.0777);Loss of glycosylation at P40 (P = 0.0777);Loss of glycosylation at P40 (P = 0.0777);Loss of glycosylation at P40 (P = 0.0777);
MVP		0.29
MPC		0.0069
ClinPred		0.18	T
GERP RS		0.55
Varity_R		0.053
gMVP		0.093

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: chr9-1051735;