14-105168369-CCAGCAG-C

Variant names:

• chr14-105168369-CCAGCAG-C
• rs587632836
• NM_002226.5:c.46_51delCTGCTG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4

The NM_002226.5(JAG2):​c.46_51delCTGCTG​(p.Leu16_Leu17del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000231 in 866,480 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: JAG2 NM_002226.5 conservative_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.33
• Publications: 0 publications found

Genes affected

JAG2 (HGNC:6189): (jagged canonical Notch ligand 2) The Notch signaling pathway is an intercellular signaling mechanism that is essential for proper embryonic development. Members of the Notch gene family encode transmembrane receptors that are critical for various cell fate decisions. The protein encoded by this gene is one of several ligands that activate Notch and related receptors. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

JAG2 Gene-Disease associations (from GenCC):

• muscular dystrophy, limb-girdle, autosomal recessive 27

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ENSG00000257622 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_002226.5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002226.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAG2	NM_002226.5	MANE Select	c.46_51delCTGCTG	p.Leu16_Leu17del	conservative_inframe_deletion	Exon 1 of 26	NP_002217.3
	JAG2	NM_145159.3		c.46_51delCTGCTG	p.Leu16_Leu17del	conservative_inframe_deletion	Exon 1 of 25	NP_660142.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAG2	ENST00000331782.8	TSL:1 MANE Select	c.46_51delCTGCTG	p.Leu16_Leu17del	conservative_inframe_deletion	Exon 1 of 26	ENSP00000328169.3
	JAG2	ENST00000347004.2	TSL:1	c.46_51delCTGCTG	p.Leu16_Leu17del	conservative_inframe_deletion	Exon 1 of 25	ENSP00000328566.2
	ENSG00000257622	ENST00000548203.1	TSL:3	n.67-10612_67-10607delCTGCTG		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000231 AC: 2 AN: 866480 Hom.: 0 AF XY: 0.00000239 AC XY: 1 AN XY: 418328

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 16338

American (AMR) AF: 0.00 AC: 0 AN: 10276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9424

East Asian (EAS) AF: 0.00 AC: 0 AN: 4384

South Asian (SAS) AF: 0.00 AC: 0 AN: 36098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4138

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1884

European-Non Finnish (NFE) AF: 0.00000265 AC: 2 AN: 754820

Other (OTH) AF: 0.00 AC: 0 AN: 29118

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3

Splicing

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

Other links and lift over

dbSNP: rs587632836; hg19: chr14-105634706;