chr14-105142930-G-A

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

3
16

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]

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=0.051897466).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
JAG2NM_002226.5 linkuse as main transcriptc.3482C>T p.Ala1161Val missense_variant 26/26 ENST00000331782.8 NP_002217.3
JAG2NM_145159.3 linkuse as main transcriptc.3368C>T p.Ala1123Val missense_variant 25/25 NP_660142.1
JAG2XM_047431352.1 linkuse as main transcriptc.3140C>T p.Ala1047Val missense_variant 25/25 XP_047287308.1
JAG2XM_047431353.1 linkuse as main transcriptc.3026C>T p.Ala1009Val 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.3482C>T p.Ala1161Val missense_variant 26/261 NM_002226.5 ENSP00000328169 P1Q9Y219-1
JAG2ENST00000347004.2 linkuse as main transcriptc.3368C>T p.Ala1123Val missense_variant 25/251 ENSP00000328566 Q9Y219-2
JAG2ENST00000546616.1 linkuse as main transcriptn.1100C>T non_coding_transcript_exon_variant 7/75

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152196
Hom.:
0
Cov.:
34
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:
15
AN:
232616
Hom.:
0
AF XY:
0.0000701
AC XY:
9
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:
73
AN:
1456082
Hom.:
0
Cov.:
30
AF XY:
0.0000525
AC XY:
38
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:
7
AN:
152196
Hom.:
0
Cov.:
34
AF XY:
0.0000538
AC XY:
4
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.:
0
Bravo
AF:
0.0000718
ExAC
AF:
0.0000761
AC:
9

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 GeneticsNov 09, 2023The 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
T
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
D
LIST_S2
Benign
0.72
T;T
M_CAP
Uncertain
0.10
D
MetaRNN
Benign
0.052
T;T
MetaSVM
Benign
-0.68
T
MutationAssessor
Benign
0.69
N;.
MutationTaster
Benign
0.63
D;D
PrimateAI
Uncertain
0.66
T
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
T
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.

Other links and lift over

dbSNP: rs778692204; hg19: chr14-105609267; API