Variant chr14-105142723-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002226.5(JAG2):c.3689A>G(p.Asn1230Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000066 in 1,607,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000067 ( 0 hom. )

Consequence

JAG2
NM_002226.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0540

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 made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.023242444).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
JAG2	NM_002226.5 linkuse as main transcript	c.3689A>G	p.Asn1230Ser	missense_variant	26/26	ENST00000331782.8
JAG2	NM_145159.3 linkuse as main transcript	c.3575A>G	p.Asn1192Ser	missense_variant	25/25
JAG2	XM_047431352.1 linkuse as main transcript	c.3347A>G	p.Asn1116Ser	missense_variant	25/25
JAG2	XM_047431353.1 linkuse as main transcript	c.3233A>G	p.Asn1078Ser	missense_variant	24/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAG2	ENST00000331782.8 linkuse as main transcript	c.3689A>G	p.Asn1230Ser	missense_variant	26/26	1	NM_002226.5	P1	Q9Y219-1
JAG2	ENST00000347004.2 linkuse as main transcript	c.3575A>G	p.Asn1192Ser	missense_variant	25/25	1			Q9Y219-2
JAG2	ENST00000546616.1 linkuse as main transcript	n.1307A>G		non_coding_transcript_exon_variant	7/7	5

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000581

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000119

AC:

AN:

235344

Hom.:

AF XY:

0.000132

AC XY:

AN XY:

129074

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000592

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000508

Gnomad SAS exome

AF:

0.000172

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000674

AC:

AN:

1455008

Hom.:

Cov.:

AF XY:

0.0000760

AC XY:

AN XY:

723366

show subpopulations

Gnomad4 AFR exome

AF:

0.0000900

Gnomad4 AMR exome

AF:

0.0000901

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000329

Gnomad4 SAS exome

AF:

0.000129

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000559

Gnomad4 OTH exome

AF:

0.0000665

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000583

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000148

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.000108

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2023

The c.3689A>G (p.N1230S) alteration is located in exon 26 (coding exon 26) of the JAG2 gene. This alteration results from a A to G substitution at nucleotide position 3689, causing the asparagine (N) at amino acid position 1230 to be replaced by a serine (S). 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

0.057

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.50

CADD

Benign

0.39

DANN

Benign

0.62

DEOGEN2

Uncertain

0.69

D;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.094

LIST_S2

Benign

0.66

T;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.023

T;T

MetaSVM

Benign

-0.70

MutationAssessor

Benign

1.3

L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.5

D;D

REVEL

Benign

0.19

Sift

Benign

0.045

D;D

Sift4G

Uncertain

0.037

D;D

Polyphen

0.0030

B;B

Vest4

0.11

MutPred

0.20

Gain of phosphorylation at N1230 (P = 0.0079);.;

MVP

0.69

MPC

0.18

ClinPred

0.025

GERP RS

-0.77

Varity_R

0.059

gMVP

0.025

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