Genetic Variant JAG2:p.Val1174Ile (chr14-105142892-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002226.5(JAG2):c.3520G>A(p.Val1174Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00051 in 1,600,202 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00035 ( 1 hom., cov: 34)

Exomes 𝑓: 0.00053 ( 1 hom. )

Consequence

JAG2
NM_002226.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.180

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018462569).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG2	NM_002226.5 link	c.3520G>A	p.Val1174Ile	missense_variant	Exon 26 of 26	ENST00000331782.8	NP_002217.3	Q9Y219-1
JAG2	NM_145159.3 link	c.3406G>A	p.Val1136Ile	missense_variant	Exon 25 of 25		NP_660142.1	Q9Y219-2
JAG2	XM_047431352.1 link	c.3178G>A	p.Val1060Ile	missense_variant	Exon 25 of 25		XP_047287308.1
JAG2	XM_047431353.1 link	c.3064G>A	p.Val1022Ile	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.3520G>A	p.Val1174Ile	missense_variant	Exon 26 of 26	1	NM_002226.5	ENSP00000328169.3	Q9Y219-1
JAG2	ENST00000347004.2 link	c.3406G>A	p.Val1136Ile	missense_variant	Exon 25 of 25	1		ENSP00000328566.2	Q9Y219-2
JAG2	ENST00000546616.1 link	n.1138G>A		non_coding_transcript_exon_variant	Exon 7 of 7	5

Frequencies

GnomAD3 genomes

AF:

0.000355

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000617

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000566

AC:

125

AN:

221040

AF XY:

0.000563

show subpopulations

Gnomad AFR exome

AF:

0.000229

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000202

Gnomad NFE exome

AF:

0.000989

Gnomad OTH exome

AF:

0.000720

GnomAD4 exome

AF:

0.000526

AC:

762

AN:

1447880

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

387

AN XY:

719196

show subpopulations

Gnomad4 AFR exome

AF:

0.0000904

AC:

AN:

33198

Gnomad4 AMR exome

AF:

0.000417

AC:

AN:

43120

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

25860

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39122

Gnomad4 SAS exome

AF:

0.000224

AC:

AN:

84802

Gnomad4 FIN exome

AF:

0.000275

AC:

AN:

50848

Gnomad4 NFE exome

AF:

0.000602

AC:

665

AN:

1105440

Gnomad4 Remaining exome

AF:

0.000519

AC:

AN:

59736

Heterozygous variant carriers

135

180

225

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000355

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000168

AC:

0.000168334

AN:

0.000168334

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.000471

AC:

0.000471342

AN:

0.000471342

Gnomad4 NFE

AF:

0.000618

AC:

0.00061752

AN:

0.00061752

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000579

Hom.:

Bravo

AF:

0.000314

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.000611

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Feb 22, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.49

CADD

Benign

1.1

DANN

Benign

0.84

DEOGEN2

Benign

0.35

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.61

T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.018

T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

0.69

N;.

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.49

N;N

REVEL

Benign

0.12

Sift

Benign

0.10

T;T

Sift4G

Benign

0.089

T;T

Polyphen

0.025

B;B

Vest4

0.060

MVP

0.24

MPC

0.20

ClinPred

0.00079

GERP RS

2.0

Varity_R

0.018

gMVP

0.012

Mutation Taster

=99/1

polymorphism

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