15-51481264-AACTTCCATTGCCATC-AACTTCCATTGCCATCACTTCCATTGCCATC

Variant names:

• chr15-51481264-A-AACTTCCATTGCCATC
• rs606231461
• NM_001378457.1:c.5827_5841dupGATGGCAATGGAAGT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_001378457.1(DMXL2):​c.5827_5841dupGATGGCAATGGAAGT​(p.Ser1947_Ser1948insAspGlyAsnGlySer) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DMXL2 NM_001378457.1 conservative_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.54
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
• 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: Unknown, AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• hearing loss, autosomal dominant 71

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000259678 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001378457.1.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378457.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMXL2	NM_001378457.1	MANE Select	c.5827_5841dupGATGGCAATGGAAGT	p.Ser1947_Ser1948insAspGlyAsnGlySer	conservative_inframe_insertion	Exon 24 of 44	NP_001365386.1	H0YLM8
	DMXL2	NM_001378458.1		c.5827_5841dupGATGGCAATGGAAGT	p.Ser1947_Ser1948insAspGlyAsnGlySer	conservative_inframe_insertion	Exon 24 of 44	NP_001365387.1
	DMXL2	NM_001174116.3		c.5827_5841dupGATGGCAATGGAAGT	p.Ser1947_Ser1948insAspGlyAsnGlySer	conservative_inframe_insertion	Exon 24 of 43	NP_001167587.1	Q8TDJ6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMXL2	ENST00000560891.6	TSL:1 MANE Select	c.5827_5841dupGATGGCAATGGAAGT	p.Ser1947_Ser1948insAspGlyAsnGlySer	conservative_inframe_insertion	Exon 24 of 44	ENSP00000453267.2	H0YLM8
	DMXL2	ENST00000543779.6	TSL:1	c.5827_5841dupGATGGCAATGGAAGT	p.Ser1947_Ser1948insAspGlyAsnGlySer	conservative_inframe_insertion	Exon 24 of 43	ENSP00000441858.2	Q8TDJ6-3
	DMXL2	ENST00000251076.9	TSL:1	c.5827_5841dupGATGGCAATGGAAGT	p.Ser1947_Ser1948insAspGlyAsnGlySer	conservative_inframe_insertion	Exon 24 of 43	ENSP00000251076.5	Q8TDJ6-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs606231461; hg19: chr15-51773461;