14-105168369-C-CCAG

Variant names:

• chr14-105168369-C-CCAG
• rs587632836
• NM_002226.5:c.49_51dupCTG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 1P and 10B. PM4_Supporting BP6_Moderate BS1 BS2

The NM_002226.5(JAG2):​c.49_51dupCTG​(p.Leu17dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0335 in 1,011,200 control chromosomes in the GnomAD database, including 456 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.024 (67 hom., cov: 30)
  • Exomes 𝑓: 0.035 (389 hom.)
• Consequence: JAG2 NM_002226.5 conservative_inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.245
• 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: Benign. The variant received -9 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_002226.5. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 14-105168369-C-CCAG is Benign according to our data. Variant chr14-105168369-C-CCAG is described in ClinVar as Benign. ClinVar VariationId is 402990.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.024 (3504/145738) while in subpopulation NFE AF = 0.0394 (2581/65506). AF 95% confidence interval is 0.0381. There are 67 homozygotes in GnomAd4. There are 1570 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 67 AR gene

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_51dupCTG	p.Leu17dup	conservative_inframe_insertion	Exon 1 of 26	NP_002217.3
	JAG2	NM_145159.3		c.49_51dupCTG	p.Leu17dup	conservative_inframe_insertion	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_51dupCTG	p.Leu17dup	conservative_inframe_insertion	Exon 1 of 26	ENSP00000328169.3
	JAG2	ENST00000347004.2	TSL:1	c.49_51dupCTG	p.Leu17dup	conservative_inframe_insertion	Exon 1 of 25	ENSP00000328566.2
	ENSG00000257622	ENST00000548203.1	TSL:3	n.67-10609_67-10607dupCTG		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0241 AC: 3503 AN: 145650 Hom.: 67 Cov.: 30

Gnomad AFR AF: 0.00773

Gnomad AMI AF: 0.0246

Gnomad AMR AF: 0.0130

Gnomad ASJ AF: 0.0234

Gnomad EAS AF: 0.000983

Gnomad SAS AF: 0.0260

Gnomad FIN AF: 0.0166

Gnomad MID AF: 0.0226

Gnomad NFE AF: 0.0394

Gnomad OTH AF: 0.0204

GnomAD2 exomes AF: 0.0198 AC: 815 AN: 41072 AF XY: 0.0231

Gnomad AFR exome AF: 0.00820

Gnomad AMR exome AF: 0.00664

Gnomad ASJ exome AF: 0.0160

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0146

Gnomad NFE exome AF: 0.0272

Gnomad OTH exome AF: 0.0165

GnomAD4 exome AF: 0.0351 AC: 30373 AN: 865462 Hom.: 389 Cov.: 12 AF XY: 0.0351 AC XY: 14673 AN XY: 417802

African (AFR) AF: 0.00429 AC: 70 AN: 16336

American (AMR) AF: 0.00847 AC: 87 AN: 10272

Ashkenazi Jewish (ASJ) AF: 0.0176 AC: 166 AN: 9418

East Asian (EAS) AF: 0.000457 AC: 2 AN: 4380

South Asian (SAS) AF: 0.0265 AC: 955 AN: 36040

European-Finnish (FIN) AF: 0.0138 AC: 57 AN: 4134

Middle Eastern (MID) AF: 0.0276 AC: 52 AN: 1884

European-Non Finnish (NFE) AF: 0.0372 AC: 28071 AN: 753924

Other (OTH) AF: 0.0314 AC: 913 AN: 29074

GnomAD4 genome AF: 0.0240 AC: 3504 AN: 145738 Hom.: 67 Cov.: 30 AF XY: 0.0221 AC XY: 1570 AN XY: 70932

African (AFR) AF: 0.00771 AC: 314 AN: 40730

American (AMR) AF: 0.0132 AC: 195 AN: 14738

Ashkenazi Jewish (ASJ) AF: 0.0234 AC: 79 AN: 3382

East Asian (EAS) AF: 0.000986 AC: 5 AN: 5070

South Asian (SAS) AF: 0.0256 AC: 122 AN: 4764

European-Finnish (FIN) AF: 0.0166 AC: 138 AN: 8332

Middle Eastern (MID) AF: 0.0245 AC: 7 AN: 286

European-Non Finnish (NFE) AF: 0.0394 AC: 2581 AN: 65506

Other (OTH) AF: 0.0202 AC: 41 AN: 2034

Alfa AF: 0.00555 Hom.: 2

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.24
Mutation Taster		=79/21	polymorphism

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;