Variant 14-105142930-G-A 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.3482C>T(p.Ala1161Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000497 in 1,608,278 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 0.000046 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

JAG2
NM_002226.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.73

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.051897466).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
JAG2	NM_002226.5 linkuse as main transcript	c.3482C>T	p.Ala1161Val	missense_variant	26/26	ENST00000331782.8	NP_002217.3
JAG2	NM_145159.3 linkuse as main transcript	c.3368C>T	p.Ala1123Val	missense_variant	25/25		NP_660142.1
JAG2	XM_047431352.1 linkuse as main transcript	c.3140C>T	p.Ala1047Val	missense_variant	25/25		XP_047287308.1
JAG2	XM_047431353.1 linkuse as main transcript	c.3026C>T	p.Ala1009Val	missense_variant	24/24		XP_047287309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAG2	ENST00000331782.8 linkuse as main transcript	c.3482C>T	p.Ala1161Val	missense_variant	26/26	1	NM_002226.5	ENSP00000328169	P1	Q9Y219-1
JAG2	ENST00000347004.2 linkuse as main transcript	c.3368C>T	p.Ala1123Val	missense_variant	25/25	1		ENSP00000328566		Q9Y219-2
JAG2	ENST00000546616.1 linkuse as main transcript	n.1100C>T		non_coding_transcript_exon_variant	7/7	5

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000645

AC:

AN:

232616

Hom.:

AF XY:

0.0000701

AC XY:

AN XY:

128380

show subpopulations

Gnomad AFR exome

AF:

0.000144

Gnomad AMR exome

AF:

0.0000295

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000665

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000890

Gnomad OTH exome

AF:

0.000175

GnomAD4 exome

AF:

0.0000501

AC:

AN:

1456082

Hom.:

Cov.:

AF XY:

0.0000525

AC XY:

AN XY:

723990

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000465

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000541

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000332

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000761

AC:

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

Nov 09, 2023

The c.3482C>T (p.A1161V) alteration is located in exon 26 (coding exon 26) of the JAG2 gene. This alteration results from a C to T substitution at nucleotide position 3482, causing the alanine (A) at amino acid position 1161 to be replaced by a valine (V). 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

0.073

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.38

CADD

Benign

9.4

DANN

Benign

0.59

DEOGEN2

Benign

0.30

T;.

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.68

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.72

T;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.052

T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

0.69

N;.

MutationTaster

Benign

0.63

D;D

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.90

N;N

REVEL

Benign

0.19

Sift

Benign

0.43

T;T

Sift4G

Benign

0.36

T;T

Polyphen

0.010

B;B

Vest4

0.039

MutPred

0.14

Loss of relative solvent accessibility (P = 0.0306);.;

MVP

0.41

MPC

0.23

ClinPred

0.015

GERP RS

2.4

Varity_R

0.016

gMVP

0.043

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