Genetic Variant DMRT2:p.Ser8Cys (chr9-1051636-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_181872.6(DMRT2):c.23C>G(p.Ser8Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,411,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. S8F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

DMRT2
NM_181872.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.325

Publications

0 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

spondylocostal dysostosis
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

DMRT2 links:

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ACMG classification

Classification was made for transcript

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=0.12120342).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMRT2	NM_181872.6 link	c.23C>G	p.Ser8Cys	missense_variant	Exon 2 of 4	ENST00000358146.7	NP_870987.2	Q9Y5R5-1Q05C20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMRT2	ENST00000358146.7 link	c.23C>G	p.Ser8Cys	missense_variant	Exon 2 of 4	1	NM_181872.6	ENSP00000350865.2		Q9Y5R5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.08e-7

AC:

AN:

1411610

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

700560

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30382

American (AMR)

AF:

0.00

AC:

AN:

40052

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24860

East Asian (EAS)

AF:

0.00

AC:

AN:

36076

South Asian (SAS)

AF:

0.0000122

AC:

AN:

82234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37190

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5678

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1096258

Other (OTH)

AF:

0.00

AC:

AN:

58880

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

9.4

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.036

.;.;T;.;.;T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.43

.;.;T;.;T;.;T

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.12

T;T;T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.1

L;L;L;L;.;L;L

PhyloP100

-0.33

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.13

.;N;N;N;N;N;N

REVEL

Benign

0.056

Sift

Uncertain

0.012

.;D;D;D;D;D;D

Sift4G

Benign

0.073

T;T;T;T;T;T;T

Polyphen

0.55

.;.;P;.;.;P;.

Vest4

0.11

MutPred

0.26

Loss of glycosylation at S8 (P = 0.0049);Loss of glycosylation at S8 (P = 0.0049);Loss of glycosylation at S8 (P = 0.0049);Loss of glycosylation at S8 (P = 0.0049);Loss of glycosylation at S8 (P = 0.0049);Loss of glycosylation at S8 (P = 0.0049);Loss of glycosylation at S8 (P = 0.0049);

MVP

0.19

MPC

0.0070

ClinPred

0.62

GERP RS

-3.8

PromoterAI

-0.0051

Neutral

(source)

Varity_R

0.073

gMVP

0.016

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over