Genetic Variant JAG2:p.Lys1203Glu (chr14-105142805-T-C) – 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.3607A>G(p.Lys1203Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000596 in 1,458,636 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: 0.000060 ( 0 hom. )

Consequence

JAG2
NM_002226.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.47

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=0.29718924).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG2	NM_002226.5 link	c.3607A>G	p.Lys1203Glu	missense_variant	Exon 26 of 26	ENST00000331782.8	NP_002217.3	Q9Y219-1
JAG2	NM_145159.3 link	c.3493A>G	p.Lys1165Glu	missense_variant	Exon 25 of 25		NP_660142.1	Q9Y219-2
JAG2	XM_047431352.1 link	c.3265A>G	p.Lys1089Glu	missense_variant	Exon 25 of 25		XP_047287308.1
JAG2	XM_047431353.1 link	c.3151A>G	p.Lys1051Glu	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.3607A>G	p.Lys1203Glu	missense_variant	Exon 26 of 26	1	NM_002226.5	ENSP00000328169.3	Q9Y219-1
JAG2	ENST00000347004.2 link	c.3493A>G	p.Lys1165Glu	missense_variant	Exon 25 of 25	1		ENSP00000328566.2	Q9Y219-2
JAG2	ENST00000546616.1 link	n.1225A>G		non_coding_transcript_exon_variant	Exon 7 of 7	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000163

AC:

AN:

245118

Hom.:

AF XY:

0.0000225

AC XY:

AN XY:

133446

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000364

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000596

AC:

AN:

1458636

Hom.:

Cov.:

AF XY:

0.0000496

AC XY:

AN XY:

725474

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000783

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.000111

Hom.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000595

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Feb 29, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Uncertain

0.079

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

D;.

Eigen

Benign

0.089

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.76

T;T

M_CAP

Uncertain

0.29

MetaRNN

Benign

0.30

T;T

MetaSVM

Uncertain

0.16

MutationAssessor

Uncertain

2.5

M;.

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-2.0

N;N

REVEL

Uncertain

0.49

Sift

Benign

0.10

T;T

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.75

P;P

Vest4

0.31

MutPred

0.25

Loss of MoRF binding (P = 0.0046);.;

MVP

0.76

MPC

0.46

ClinPred

0.43

GERP RS

4.8

Varity_R

0.28

gMVP

0.12

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