14-105142709-C-T

Position:

chr14-105142709-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_002226.5(JAG2):c.3703G>A(p.Ala1235Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000517 in 1,601,026 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0024 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00032 ( 3 hom. )

Consequence

JAG2
NM_002226.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.724

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0060788095).

BP6

Variant 14-105142709-C-T is Benign according to our data. Variant chr14-105142709-C-T is described in ClinVar as [Benign]. Clinvar id is 725844.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
JAG2	NM_002226.5 linkuse as main transcript	c.3703G>A	p.Ala1235Thr	missense_variant	26/26	ENST00000331782.8	NP_002217.3
JAG2	NM_145159.3 linkuse as main transcript	c.3589G>A	p.Ala1197Thr	missense_variant	25/25		NP_660142.1
JAG2	XM_047431352.1 linkuse as main transcript	c.3361G>A	p.Ala1121Thr	missense_variant	25/25		XP_047287308.1
JAG2	XM_047431353.1 linkuse as main transcript	c.3247G>A	p.Ala1083Thr	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.3703G>A	p.Ala1235Thr	missense_variant	26/26	1	NM_002226.5	ENSP00000328169	P1	Q9Y219-1
JAG2	ENST00000347004.2 linkuse as main transcript	c.3589G>A	p.Ala1197Thr	missense_variant	25/25	1		ENSP00000328566		Q9Y219-2
JAG2	ENST00000546616.1 linkuse as main transcript	n.1321G>A		non_coding_transcript_exon_variant	7/7	5

Frequencies

GnomAD3 genomes

AF:

0.00237

AC:

361

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00813

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000719

AC:

160

AN:

222602

Hom.:

AF XY:

0.000457

AC XY:

AN XY:

122408

show subpopulations

Gnomad AFR exome

AF:

0.00939

Gnomad AMR exome

AF:

0.000484

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000354

Gnomad SAS exome

AF:

0.000216

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000163

Gnomad OTH exome

AF:

0.000180

GnomAD4 exome

AF:

0.000322

AC:

466

AN:

1448706

Hom.:

Cov.:

AF XY:

0.000293

AC XY:

211

AN XY:

719590

show subpopulations

Gnomad4 AFR exome

AF:

0.0106

Gnomad4 AMR exome

AF:

0.000433

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000766

Gnomad4 SAS exome

AF:

0.000155

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000353

Gnomad4 OTH exome

AF:

0.000652

GnomAD4 genome

AF:

0.00238

AC:

362

AN:

152320

Hom.:

Cov.:

AF XY:

0.00224

AC XY:

167

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00813

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000364

Hom.:

Bravo

AF:

0.00297

ESP6500AA

AF:

0.00853

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.000734

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 24, 2018

- -

JAG2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 16, 2019

This variant is classified as 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

0.068

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.45

CADD

Benign

2.8

DANN

Benign

0.91

DEOGEN2

Benign

0.30

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.092

LIST_S2

Benign

0.46

T;T

MetaRNN

Benign

0.0061

T;T

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.1

M;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.46

N;N

REVEL

Benign

0.17

Sift

Benign

0.25

T;T

Sift4G

Benign

0.23

T;T

Polyphen

0.017

B;B

Vest4

0.020

MVP

0.52

MPC

0.23

ClinPred

0.0035

GERP RS

0.57

Varity_R

0.019

gMVP

0.0075

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