chr14-105142777-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

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 (no stars).

Frequency

Genomes: 𝑓 0.00089 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

JAG2
NM_002226.5 missense

Scores

1
4
14

Clinical Significance

Likely benign no assertion criteria provided 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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 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 no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
JAG2NM_002226.5 linkuse as main transcriptc.3635C>T p.Pro1212Leu missense_variant 26/26 ENST00000331782.8 NP_002217.3
JAG2NM_145159.3 linkuse as main transcriptc.3521C>T p.Pro1174Leu missense_variant 25/25 NP_660142.1
JAG2XM_047431352.1 linkuse as main transcriptc.3293C>T p.Pro1098Leu missense_variant 25/25 XP_047287308.1
JAG2XM_047431353.1 linkuse as main transcriptc.3179C>T p.Pro1060Leu 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.3635C>T p.Pro1212Leu missense_variant 26/261 NM_002226.5 ENSP00000328169 P1Q9Y219-1
JAG2ENST00000347004.2 linkuse as main transcriptc.3521C>T p.Pro1174Leu missense_variant 25/251 ENSP00000328566 Q9Y219-2
JAG2ENST00000546616.1 linkuse as main transcriptn.1253C>T non_coding_transcript_exon_variant 7/75

Frequencies

GnomAD3 genomes
AF:
0.000874
AC:
133
AN:
152222
Hom.:
0
Cov.:
33
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:
60
AN:
243982
Hom.:
0
AF XY:
0.000210
AC XY:
28
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.:
0
Cov.:
30
AF XY:
0.000103
AC XY:
75
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.:
0
Cov.:
33
AF XY:
0.000886
AC XY:
66
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.:
0
Bravo
AF:
0.00100
ESP6500AA
AF:
0.00137
AC:
6
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000207
AC:
25
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

JAG2-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesApr 17, 2023This 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
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
20
DANN
Benign
0.96
DEOGEN2
Uncertain
0.50
D;.
Eigen
Benign
-0.15
Eigen_PC
Benign
-0.11
FATHMM_MKL
Benign
0.48
N
LIST_S2
Benign
0.70
T;T
M_CAP
Pathogenic
0.38
D
MetaRNN
Benign
0.010
T;T
MetaSVM
Benign
-0.61
T
MutationAssessor
Uncertain
2.7
M;.
MutationTaster
Benign
1.0
N;N
PrimateAI
Uncertain
0.55
T
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
T
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.

Other links and lift over

dbSNP: rs202039687; hg19: chr14-105609114; COSMIC: COSV59306033; COSMIC: COSV59306033; API