Genetic Variant JAG2:p.Glu1163Lys (chr14-105142925-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_002226.5(JAG2):c.3487G>A(p.Glu1163Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000549 in 1,455,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

JAG2
NM_002226.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.22

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3427512).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG2	NM_002226.5 link	c.3487G>A	p.Glu1163Lys	missense_variant	Exon 26 of 26	ENST00000331782.8	NP_002217.3	Q9Y219-1
JAG2	NM_145159.3 link	c.3373G>A	p.Glu1125Lys	missense_variant	Exon 25 of 25		NP_660142.1	Q9Y219-2
JAG2	XM_047431352.1 link	c.3145G>A	p.Glu1049Lys	missense_variant	Exon 25 of 25		XP_047287308.1
JAG2	XM_047431353.1 link	c.3031G>A	p.Glu1011Lys	missense_variant	Exon 24 of 24		XP_047287309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
JAG2	ENST00000331782.8 link	c.3487G>A	p.Glu1163Lys	missense_variant	Exon 26 of 26	1	NM_002226.5	ENSP00000328169.3	Q9Y219-1
JAG2	ENST00000347004.2 link	c.3373G>A	p.Glu1125Lys	missense_variant	Exon 25 of 25	1		ENSP00000328566.2	Q9Y219-2
JAG2	ENST00000546616.1 link	n.1105G>A		non_coding_transcript_exon_variant	Exon 7 of 7	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000214

AC:

AN:

233384

Hom.:

AF XY:

0.00000778

AC XY:

AN XY:

128560

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000296

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000114

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000480

Gnomad NFE exome

AF:

0.00000983

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000549

AC:

AN:

1455994

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

723970

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000541

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3487G>A (p.E1163K) alteration is located in exon 26 (coding exon 26) of the JAG2 gene. This alteration results from a G to A substitution at nucleotide position 3487, causing the glutamic acid (E) at amino acid position 1163 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.42

T;.

Eigen

Benign

-0.058

Eigen_PC

Benign

-0.050

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.86

D;D

M_CAP

Pathogenic

0.46

MetaRNN

Benign

0.34

T;T

MetaSVM

Uncertain

-0.17

MutationAssessor

Uncertain

2.4

M;.

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.24

Sift

Benign

0.071

T;T

Sift4G

Benign

0.061

T;T

Polyphen

0.76

P;P

Vest4

0.15

MutPred

0.25

Gain of ubiquitination at E1163 (P = 0.0101);.;

MVP

0.69

MPC

0.35

ClinPred

0.17

GERP RS

4.3

Varity_R

0.099

gMVP

0.20

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over