Variant 14-105142777-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_002226.5(JAG2):c.3635C>T(p.Pro1212Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000178 in 1,610,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P1212P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00089 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

JAG2
NM_002226.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.74

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 Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.010270774).

BP6

Variant 14-105142777-G-A is Benign according to our data. Variant chr14-105142777-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3036459.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
JAG2	NM_002226.5 linkuse as main transcript	c.3635C>T	p.Pro1212Leu	missense_variant	26/26	ENST00000331782.8
JAG2	NM_145159.3 linkuse as main transcript	c.3521C>T	p.Pro1174Leu	missense_variant	25/25
JAG2	XM_047431352.1 linkuse as main transcript	c.3293C>T	p.Pro1098Leu	missense_variant	25/25
JAG2	XM_047431353.1 linkuse as main transcript	c.3179C>T	p.Pro1060Leu	missense_variant	24/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAG2	ENST00000331782.8 linkuse as main transcript	c.3635C>T	p.Pro1212Leu	missense_variant	26/26	1	NM_002226.5	P1	Q9Y219-1
JAG2	ENST00000347004.2 linkuse as main transcript	c.3521C>T	p.Pro1174Leu	missense_variant	25/25	1			Q9Y219-2
JAG2	ENST00000546616.1 linkuse as main transcript	n.1253C>T		non_coding_transcript_exon_variant	7/7	5

Frequencies

GnomAD3 genomes

AF:

0.000874

AC:

133

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000246

AC:

AN:

243982

Hom.:

AF XY:

0.000210

AC XY:

AN XY:

133094

show subpopulations

Gnomad AFR exome

AF:

0.00300

Gnomad AMR exome

AF:

0.000321

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000333

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000183

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000104

AC:

151

AN:

1458518

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

725416

show subpopulations

Gnomad4 AFR exome

AF:

0.00320

Gnomad4 AMR exome

AF:

0.000314

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000466

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000893

AC:

136

AN:

152340

Hom.:

Cov.:

AF XY:

0.000886

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00296

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000533

Hom.:

Bravo

AF:

0.00100

ESP6500AA

AF:

0.00137

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000207

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

JAG2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 17, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Uncertain

0.50

D;.

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.70

T;T

M_CAP

Pathogenic

0.38

MetaRNN

Benign

0.010

T;T

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.7

M;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.4

N;N

REVEL

Benign

0.17

Sift

Benign

0.68

T;T

Sift4G

Benign

0.53

T;T

Polyphen

0.61

P;B

Vest4

0.037

MVP

0.78

MPC

0.32

ClinPred

0.033

GERP RS

3.9

Varity_R

0.036

gMVP

0.045

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