chr15-51507191-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001378457.1(DMXL2):c.2707A>G(p.Asn903Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000946 in 1,611,372 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. N903N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0053 ( 8 hom., cov: 32)

Exomes 𝑓: 0.00049 ( 4 hom. )

Consequence

DMXL2
NM_001378457.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.02

Publications

3 publications found

Variant links:

Genes affected

DMXL2 (HGNC:2938): (Dmx like 2) This gene encodes a protein with 12 WD domains. Proteins with WD domains are involved in many functions including participation in signal transduction pathways. Participation of the encoded protein in regulation of the Notch signaling pathway has been demonstrated in vitro using several human cell lines (PMID:20810660). A gene encoding a similar protein is located on chromosome 5. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

DMXL2 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy, 81
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae)
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
polyendocrine-polyneuropathy syndrome
Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
hearing loss, autosomal dominant 71
Inheritance: AD, Unknown Classification: LIMITED Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae)
nonsyndromic genetic hearing loss
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

DMXL2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004383117).

BP6

Variant 15-51507191-T-C is Benign according to our data. Variant chr15-51507191-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00528 (804/152334) while in subpopulation AFR AF = 0.0179 (746/41580). AF 95% confidence interval is 0.0169. There are 8 homozygotes in GnomAd4. There are 350 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AD,AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMXL2	NM_001378457.1 link	c.2707A>G	p.Asn903Asp	missense_variant	Exon 16 of 44	ENST00000560891.6	NP_001365386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
DMXL2	ENST00000560891.6 link	c.2707A>G	p.Asn903Asp	missense_variant	Exon 16 of 44	1	NM_001378457.1	ENSP00000453267.2
DMXL2	ENST00000543779.6 link	c.2707A>G	p.Asn903Asp	missense_variant	Exon 16 of 43	1		ENSP00000441858.2
DMXL2	ENST00000251076.9 link	c.2707A>G	p.Asn903Asp	missense_variant	Exon 16 of 43	1		ENSP00000251076.5
DMXL2	ENST00000449909.7 link	c.2707A>G	p.Asn903Asp	missense_variant	Exon 16 of 41	1		ENSP00000400855.3

Frequencies

GnomAD3 genomes

AF:

0.00529

AC:

805

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0180

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

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:

0.0000147

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00135

AC:

338

AN:

250648

AF XY:

0.00102

show subpopulations

Gnomad AFR exome

AF:

0.0179

Gnomad AMR exome

AF:

0.000930

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.000981

GnomAD4 exome

AF:

0.000493

AC:

720

AN:

1459038

Hom.:

Cov.:

AF XY:

0.000435

AC XY:

316

AN XY:

725968

show subpopulations

African (AFR)

AF:

0.0177

AC:

590

AN:

33396

American (AMR)

AF:

0.000717

AC:

AN:

44646

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.00

AC:

AN:

39552

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86078

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

52934

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.0000288

AC:

AN:

1110320

Other (OTH)

AF:

0.000929

AC:

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

104

139

174

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00528

AC:

804

AN:

152334

Hom.:

Cov.:

AF XY:

0.00470

AC XY:

350

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.0179

AC:

746

AN:

41580

American (AMR)

AF:

0.00327

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68022

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

118

158

197

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00197

Hom.:

Bravo

AF:

0.00574

ESP6500AA

AF:

0.0207

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00165

AC:

200

Asia WGS

AF:

0.00173

AC:

AN:

3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 14, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.016

T;.;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.93

D;D;D

MetaRNN

Benign

0.0044

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

M;M;M

PhyloP100

3.0

PrimateAI

Benign

0.48

PROVEAN

Benign

-2.0

N;N;N

REVEL

Benign

0.049

Sift

Benign

0.33

T;T;T

Sift4G

Benign

0.31

.;.;T

Polyphen

0.049

B;.;.

Vest4

0.26

MVP

0.57

MPC

0.26

ClinPred

0.021

GERP RS

2.5

Varity_R

0.12

gMVP

0.24

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over