14-105168369-CCAGCAG-CCAG

Variant names:

• chr14-105168369-CCAG-C
• rs587632836
• NM_002226.5:c.49_51delCTG

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_002226.5(JAG2):​c.49_51delCTG​(p.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 0.00298 in 985,194 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: 𝑓 0.0000069 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0035 (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 3 ACMG points.

• PM2: Variant has high frequency in the AMR (0.0102) population. However there is too low homozygotes in high coverage region: (expected more than 2, got 0).
• PM4: Nonframeshift variant in NON repetitive region in NM_002226.5. Strenght limited to Supporting due to length of the change: 1aa.

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.49_51delCTG	p.Leu17del	conservative_inframe_deletion	Exon 1 of 26	NP_002217.3
	JAG2	NM_145159.3		c.49_51delCTG	p.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.49_51delCTG	p.Leu17del	conservative_inframe_deletion	Exon 1 of 26	ENSP00000328169.3
	JAG2	ENST00000347004.2	TSL:1	c.49_51delCTG	p.Leu17del	conservative_inframe_deletion	Exon 1 of 25	ENSP00000328566.2
	ENSG00000257622	ENST00000548203.1	TSL:3	n.67-10609_67-10607delCTG		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000687 AC: 1 AN: 145654 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00728 AC: 299 AN: 41072 AF XY: 0.00790

Gnomad AFR exome AF: 0.00205

Gnomad AMR exome AF: 0.00534

Gnomad ASJ exome AF: 0.00674

Gnomad EAS exome AF: 0.0233

Gnomad FIN exome AF: 0.00556

Gnomad NFE exome AF: 0.00854

Gnomad OTH exome AF: 0.00236

GnomAD4 exome AF: 0.00350 AC: 2938 AN: 839452 Hom.: 0 AF XY: 0.00377 AC XY: 1525 AN XY: 404600

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

African (AFR) AF: 0.00341 AC: 54 AN: 15842

American (AMR) AF: 0.0120 AC: 114 AN: 9530

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 62 AN: 8978

East Asian (EAS) AF: 0.00405 AC: 17 AN: 4200

South Asian (SAS) AF: 0.00874 AC: 299 AN: 34214

European-Finnish (FIN) AF: 0.00866 AC: 34 AN: 3924

Middle Eastern (MID) AF: 0.00110 AC: 2 AN: 1820

European-Non Finnish (NFE) AF: 0.00307 AC: 2249 AN: 732728

Other (OTH) AF: 0.00379 AC: 107 AN: 28216

⚠️ 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 AF: 0.00000686 AC: 1 AN: 145742 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 70932

African (AFR) AF: 0.0000246 AC: 1 AN: 40730

American (AMR) AF: 0.00 AC: 0 AN: 14738

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3382

East Asian (EAS) AF: 0.00 AC: 0 AN: 5070

South Asian (SAS) AF: 0.00 AC: 0 AN: 4764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65512

Other (OTH) AF: 0.00 AC: 0 AN: 2032

Alfa AF: 0.00 Hom.: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587632836; hg19: chr14-105634706;