15-51499362-A-G

Variant names:

• chr15-51499362-A-G
• rs12102203
• NM_001378457.1:c.3862T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378457.1(DMXL2):​c.3862T>C​(p.Ser1288Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.504 in 1,613,468 control chromosomes in the GnomAD database, including 206,286 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18567 hom., cov: 32)
  • Exomes 𝑓: 0.51 (187719 hom.)
• Consequence: DMXL2 NM_001378457.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.269
• Publications: 43 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0010027885).
• BP6: Variant 15-51499362-A-G is Benign according to our data. Variant chr15-51499362-A-G is described in ClinVar as Benign. ClinVar VariationId is 1255511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.516 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMXL2	NM_001378457.1	c.3862T>C	p.Ser1288Pro	missense_variant	Exon 18 of 44	ENST00000560891.6	NP_001365386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMXL2	ENST00000560891.6	c.3862T>C	p.Ser1288Pro	missense_variant	Exon 18 of 44	1	NM_001378457.1	ENSP00000453267.2
DMXL2	ENST00000543779.6	c.3862T>C	p.Ser1288Pro	missense_variant	Exon 18 of 43	1		ENSP00000441858.2
DMXL2	ENST00000251076.9	c.3862T>C	p.Ser1288Pro	missense_variant	Exon 18 of 43	1		ENSP00000251076.5
DMXL2	ENST00000449909.7	c.2765-4228T>C		intron_variant	Intron 16 of 40	1		ENSP00000400855.3

Frequencies

GnomAD3 genomes AF: 0.490 AC: 74459 AN: 151852 Hom.: 18548 Cov.: 32

Gnomad AFR AF: 0.444

Gnomad AMI AF: 0.705

Gnomad AMR AF: 0.501

Gnomad ASJ AF: 0.386

Gnomad EAS AF: 0.432

Gnomad SAS AF: 0.424

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.520

Gnomad OTH AF: 0.477

GnomAD2 exomes AF: 0.492 AC: 123222 AN: 250686 AF XY: 0.488

Gnomad AFR exome AF: 0.442

Gnomad AMR exome AF: 0.519

Gnomad ASJ exome AF: 0.389

Gnomad EAS exome AF: 0.416

Gnomad FIN exome AF: 0.548

Gnomad NFE exome AF: 0.520

Gnomad OTH exome AF: 0.474

GnomAD4 exome AF: 0.506 AC: 739086 AN: 1461498 Hom.: 187719 Cov.: 55 AF XY: 0.503 AC XY: 366016 AN XY: 727048

African (AFR) AF: 0.449 AC: 15021 AN: 33480

American (AMR) AF: 0.518 AC: 23160 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 10190 AN: 26130

East Asian (EAS) AF: 0.443 AC: 17587 AN: 39696

South Asian (SAS) AF: 0.431 AC: 37181 AN: 86250

European-Finnish (FIN) AF: 0.552 AC: 29325 AN: 53150

Middle Eastern (MID) AF: 0.448 AC: 2585 AN: 5768

European-Non Finnish (NFE) AF: 0.517 AC: 574641 AN: 1111914

Other (OTH) AF: 0.487 AC: 29396 AN: 60390

GnomAD4 genome AF: 0.490 AC: 74527 AN: 151970 Hom.: 18567 Cov.: 32 AF XY: 0.489 AC XY: 36348 AN XY: 74280

African (AFR) AF: 0.444 AC: 18400 AN: 41436

American (AMR) AF: 0.501 AC: 7652 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.386 AC: 1338 AN: 3470

East Asian (EAS) AF: 0.433 AC: 2231 AN: 5158

South Asian (SAS) AF: 0.425 AC: 2045 AN: 4816

European-Finnish (FIN) AF: 0.542 AC: 5719 AN: 10556

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.520 AC: 35350 AN: 67948

Other (OTH) AF: 0.481 AC: 1016 AN: 2114

Alfa AF: 0.498 Hom.: 60343

Bravo AF: 0.488

TwinsUK AF: 0.507 AC: 1879

ALSPAC AF: 0.521 AC: 2009

ESP6500AA AF: 0.433 AC: 1902

ESP6500EA AF: 0.505 AC: 4332

ExAC AF: 0.492 AC: 59752

Asia WGS AF: 0.418 AC: 1452 AN: 3478

EpiCase AF: 0.504

EpiControl AF: 0.495

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Developmental and epileptic encephalopathy, 81 Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Polyendocrine-polyneuropathy syndrome Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hearing loss, autosomal dominant 71 Benign:1

Jul 30, 2021

Genome-Nilou Lab

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	0.055
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	14
DANN	Benign	0.87
DEOGEN2	Benign	0.015	T;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.080	T;T
MetaRNN	Benign	0.0010	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.40	N;N
PhyloP100		0.27
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.020	N;N
REVEL	Benign	0.027
Sift	Benign	0.23	T;T
Sift4G	Pathogenic	0.0	.;.
Vest4		0.030
ClinPred		0.0071	T
GERP RS		1.7
Varity_R		0.085
gMVP		0.21
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12102203; hg19: chr15-51791559; COSMIC: COSV51842654; COSMIC: COSV51842654;