chr14-105142792-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002226.5(JAG2):​c.3620G>A​(p.Arg1207His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,610,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

JAG2
NM_002226.5 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.90
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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.072648734).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
JAG2NM_002226.5 linkuse as main transcriptc.3620G>A p.Arg1207His missense_variant 26/26 ENST00000331782.8 NP_002217.3
JAG2NM_145159.3 linkuse as main transcriptc.3506G>A p.Arg1169His missense_variant 25/25 NP_660142.1
JAG2XM_047431352.1 linkuse as main transcriptc.3278G>A p.Arg1093His missense_variant 25/25 XP_047287308.1
JAG2XM_047431353.1 linkuse as main transcriptc.3164G>A p.Arg1055His 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.3620G>A p.Arg1207His missense_variant 26/261 NM_002226.5 ENSP00000328169 P1Q9Y219-1
JAG2ENST00000347004.2 linkuse as main transcriptc.3506G>A p.Arg1169His missense_variant 25/251 ENSP00000328566 Q9Y219-2
JAG2ENST00000546616.1 linkuse as main transcriptn.1238G>A non_coding_transcript_exon_variant 7/75

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152230
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000410
AC:
1
AN:
243908
Hom.:
0
AF XY:
0.00000752
AC XY:
1
AN XY:
132924
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000292
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000185
AC:
27
AN:
1458394
Hom.:
0
Cov.:
30
AF XY:
0.0000124
AC XY:
9
AN XY:
725344
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000207
Gnomad4 OTH exome
AF:
0.0000332
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152230
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74374
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

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 GeneticsJan 17, 2024The c.3620G>A (p.R1207H) alteration is located in exon 26 (coding exon 26) of the JAG2 gene. This alteration results from a G to A substitution at nucleotide position 3620, causing the arginine (R) at amino acid position 1207 to be replaced by a histidine (H). 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
0.059
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
12
DANN
Benign
0.79
DEOGEN2
Uncertain
0.43
T;.
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.015
N
LIST_S2
Benign
0.52
T;T
M_CAP
Benign
0.065
D
MetaRNN
Benign
0.073
T;T
MetaSVM
Benign
-0.80
T
MutationAssessor
Benign
0.0
N;.
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-1.8
N;N
REVEL
Benign
0.17
Sift
Benign
0.25
T;T
Sift4G
Benign
0.17
T;T
Polyphen
0.0
B;B
Vest4
0.028
MutPred
0.24
Loss of MoRF binding (P = 0.0037);.;
MVP
0.44
MPC
0.29
ClinPred
0.017
T
GERP RS
2.0
Varity_R
0.015
gMVP
0.015

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: rs1378403382; hg19: chr14-105609129; API