Genetic Variant DMRT2:p.Glu458Gln (chr9-1056959-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_181872.6(DMRT2):c.1372G>C(p.Glu458Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.123 in 1,613,972 control chromosomes in the GnomAD database, including 13,569 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.11 ( 1116 hom., cov: 32)

Exomes 𝑓: 0.12 ( 12453 hom. )

Consequence

DMRT2
NM_181872.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.27

Publications

27 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014864802).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMRT2	NM_181872.6 link	c.1372G>C	p.Glu458Gln	missense_variant	Exon 4 of 4	ENST00000358146.7	NP_870987.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMRT2	ENST00000358146.7 link	c.1372G>C	p.Glu458Gln	missense_variant	Exon 4 of 4	1	NM_181872.6	ENSP00000350865.2

Frequencies

GnomAD3 genomes

AF:

0.110

AC:

16704

AN:

151976

Hom.:

1116

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0575

Gnomad AMI

AF:

0.0493

Gnomad AMR

AF:

0.0849

Gnomad ASJ

AF:

0.137

Gnomad EAS

AF:

0.131

Gnomad SAS

AF:

0.212

Gnomad FIN

AF:

0.241

Gnomad MID

AF:

0.193

Gnomad NFE

AF:

0.118

Gnomad OTH

AF:

0.0957

GnomAD2 exomes

AF:

0.133

AC:

33551

AN:

251478

AF XY:

0.140

show subpopulations

Gnomad AFR exome

AF:

0.0535

Gnomad AMR exome

AF:

0.0734

Gnomad ASJ exome

AF:

0.126

Gnomad EAS exome

AF:

0.132

Gnomad FIN exome

AF:

0.227

Gnomad NFE exome

AF:

0.125

Gnomad OTH exome

AF:

0.128

GnomAD4 exome

AF:

0.124

AC:

181543

AN:

1461878

Hom.:

12453

Cov.:

AF XY:

0.128

AC XY:

92987

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.0536

AC:

1794

AN:

33480

American (AMR)

AF:

0.0756

AC:

3382

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.122

AC:

3187

AN:

26136

East Asian (EAS)

AF:

0.135

AC:

5346

AN:

39698

South Asian (SAS)

AF:

0.215

AC:

18578

AN:

86256

European-Finnish (FIN)

AF:

0.217

AC:

11574

AN:

53420

Middle Eastern (MID)

AF:

0.156

AC:

899

AN:

5768

European-Non Finnish (NFE)

AF:

0.116

AC:

129531

AN:

1112000

Other (OTH)

AF:

0.120

AC:

7252

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

11070

22140

33211

44281

55351

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4688

9376

14064

18752

23440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.110

AC:

16695

AN:

152094

Hom.:

1116

Cov.:

AF XY:

0.118

AC XY:

8772

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.0575

AC:

2385

AN:

41506

American (AMR)

AF:

0.0847

AC:

1294

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.137

AC:

476

AN:

3472

East Asian (EAS)

AF:

0.131

AC:

679

AN:

5176

South Asian (SAS)

AF:

0.212

AC:

1021

AN:

4818

European-Finnish (FIN)

AF:

0.241

AC:

2540

AN:

10528

Middle Eastern (MID)

AF:

0.190

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.118

AC:

8000

AN:

67994

Other (OTH)

AF:

0.0942

AC:

199

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

754

1508

2261

3015

3769

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

194

388

582

776

970

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.116

Hom.:

830

Bravo

AF:

0.0923

TwinsUK

AF:

0.120

AC:

446

ALSPAC

AF:

0.112

AC:

433

ESP6500AA

AF:

0.0524

AC:

231

ESP6500EA

AF:

0.117

AC:

1008

ExAC

AF:

0.135

AC:

16424

Asia WGS

AF:

0.159

AC:

552

AN:

3478

EpiCase

AF:

0.121

EpiControl

AF:

0.126

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

T;.;T

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

D;D;.

MetaRNN

Benign

0.0015

T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.6

M;.;M

PhyloP100

7.3

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.86

N;.;N

REVEL

Benign

0.14

Sift

Uncertain

0.0030

D;.;D

Sift4G

Benign

0.13

T;T;T

Polyphen

0.99

D;.;D

Vest4

0.13

MPC

0.027

ClinPred

0.027

GERP RS

5.8

Varity_R

0.23

gMVP

0.12

Mutation Taster

=94/6

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over