14-105142898-C-A

Variant summary

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

The NM_002226.5(JAG2):​c.3514G>T​(p.Ala1172Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000312 in 1,600,686 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 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

JAG2
NM_002226.5 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.263
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]

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=0.030722797).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
JAG2NM_002226.5 linkuse as main transcriptc.3514G>T p.Ala1172Ser missense_variant 26/26 ENST00000331782.8 NP_002217.3
JAG2NM_145159.3 linkuse as main transcriptc.3400G>T p.Ala1134Ser missense_variant 25/25 NP_660142.1
JAG2XM_047431352.1 linkuse as main transcriptc.3172G>T p.Ala1058Ser missense_variant 25/25 XP_047287308.1
JAG2XM_047431353.1 linkuse as main transcriptc.3058G>T p.Ala1020Ser missense_variant 24/24 XP_047287309.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
JAG2ENST00000331782.8 linkuse as main transcriptc.3514G>T p.Ala1172Ser missense_variant 26/261 NM_002226.5 ENSP00000328169 P1Q9Y219-1
JAG2ENST00000347004.2 linkuse as main transcriptc.3400G>T p.Ala1134Ser missense_variant 25/251 ENSP00000328566 Q9Y219-2
JAG2ENST00000546616.1 linkuse as main transcriptn.1132G>T non_coding_transcript_exon_variant 7/75

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152186
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000452
AC:
1
AN:
221106
Hom.:
0
AF XY:
0.00000826
AC XY:
1
AN XY:
121002
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:
0.0000347
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000207
AC:
3
AN:
1448388
Hom.:
0
Cov.:
30
AF XY:
0.00000278
AC XY:
2
AN XY:
719452
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:
9.04e-7
Gnomad4 OTH exome
AF:
0.0000335
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152298
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.0000481
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:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.0000168
AC:
2
Asia WGS
AF:
0.000578
AC:
2
AN:
3474

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 submitterclinical testingAmbry GeneticsAug 29, 2023The c.3514G>T (p.A1172S) alteration is located in exon 26 (coding exon 26) of the JAG2 gene. This alteration results from a G to T substitution at nucleotide position 3514, causing the alanine (A) at amino acid position 1172 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
0.085
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.45
CADD
Benign
0.086
DANN
Benign
0.28
DEOGEN2
Benign
0.28
T;.
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.23
N
LIST_S2
Benign
0.56
T;T
M_CAP
Uncertain
0.10
D
MetaRNN
Benign
0.031
T;T
MetaSVM
Benign
-0.74
T
MutationAssessor
Benign
0.69
N;.
MutationTaster
Benign
1.0
N;N
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
-0.010
N;N
REVEL
Benign
0.21
Sift
Benign
0.85
T;T
Sift4G
Benign
0.98
T;T
Polyphen
0.10
B;B
Vest4
0.065
MutPred
0.13
Gain of phosphorylation at A1172 (P = 0.006);.;
MVP
0.50
MPC
0.25
ClinPred
0.054
T
GERP RS
2.4
Varity_R
0.015
gMVP
0.016

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.

Other links and lift over

dbSNP: rs587647951; hg19: chr14-105609235; API