14-105150705-C-A

Variant names:

• chr14-105150705-C-A
• rs1057744
• NM_002226.5:c.1501G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_002226.5(JAG2):​c.1501G>T​(p.Glu501*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,408,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: JAG2 NM_002226.5 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0740
• 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]

MIR6765 (HGNC:50030): (microRNA 6765) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

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.1501G>T	p.Glu501*	stop_gained	Exon 12 of 26	NP_002217.3
	JAG2	NM_145159.3		c.1387G>T	p.Glu463*	stop_gained	Exon 11 of 25	NP_660142.1
	MIR6765	NR_106823.1		n.*73G>T		downstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAG2	ENST00000331782.8	TSL:1 MANE Select	c.1501G>T	p.Glu501*	stop_gained	Exon 12 of 26	ENSP00000328169.3
	JAG2	ENST00000347004.2	TSL:1	c.1387G>T	p.Glu463*	stop_gained	Exon 11 of 25	ENSP00000328566.2
	MIR6765	ENST00000614092.1	TSL:6	n.*73G>T		downstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1408244 Hom.: 0 Cov.: 58 AF XY: 0.00000144 AC XY: 1 AN XY: 695742

African (AFR) AF: 0.00 AC: 0 AN: 32048

American (AMR) AF: 0.00 AC: 0 AN: 36942

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25260

East Asian (EAS) AF: 0.00 AC: 0 AN: 36626

South Asian (SAS) AF: 0.00 AC: 0 AN: 80302

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 9.22e-7 AC: 1 AN: 1084684

Other (OTH) AF: 0.00 AC: 0 AN: 58358

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Benign	0.15
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.059	N
PhyloP100		0.074
Vest4		0.72
GERP RS		1.4
Mutation Taster		=25/175	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1057744; hg19: chr14-105617042;