14-105142709-C-T

Variant names:

• chr14-105142709-C-T
• rs199682063
• NM_002226.5:c.3703G>A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

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
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.724

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]

ACMG classification

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 rank	MANE	Protein	UniProt
JAG2	NM_002226.5	c.3703G>A	p.Ala1235Thr	missense_variant	Exon 26 of 26	ENST00000331782.8	NP_002217.3
JAG2	NM_145159.3	c.3589G>A	p.Ala1197Thr	missense_variant	Exon 25 of 25		NP_660142.1
JAG2	XM_047431352.1	c.3361G>A	p.Ala1121Thr	missense_variant	Exon 25 of 25		XP_047287308.1
JAG2	XM_047431353.1	c.3247G>A	p.Ala1083Thr	missense_variant	Exon 24 of 24		XP_047287309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAG2	ENST00000331782.8	c.3703G>A	p.Ala1235Thr	missense_variant	Exon 26 of 26	1	NM_002226.5	ENSP00000328169.3
JAG2	ENST00000347004.2	c.3589G>A	p.Ala1197Thr	missense_variant	Exon 25 of 25	1		ENSP00000328566.2
JAG2	ENST00000546616.1	n.1321G>A		non_coding_transcript_exon_variant	Exon 7 of 7	5

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 361 AN: 152202 Hom.: 3 Cov.: 33

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.: 1 AF XY: 0.000457 AC XY: 56 AN XY: 122408

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.: 3 Cov.: 30 AF XY: 0.000293 AC XY: 211 AN XY: 719590

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.: 3 Cov.: 33 AF XY: 0.00224 AC XY: 167 AN XY: 74474

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.: 0

Bravo AF: 0.00297

ESP6500AA AF: 0.00853 AC: 37

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000734 AC: 88

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 24, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

JAG2-related disorder Benign:1

Dec 16, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	T
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	N
LIST_S2	Benign	0.46	T;T
MetaRNN	Benign	0.0061	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Benign	0.37	T
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	T
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

Other links and lift over

dbSNP: rs199682063; hg19: chr14-105609046; COSMIC: COSV59313129; COSMIC: COSV59313129;