14-105149311-C-T

Position:

• chr14-105149311-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002226.5(JAG2):​c.1612G>A​(p.Asp538Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,612,528 control chromosomes in the GnomAD database, including 15,743 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.10 (998 hom., cov: 30)
  • Exomes 𝑓: 0.14 (14745 hom.)
• Consequence: JAG2 NM_002226.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.26

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018466711).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAG2	NM_002226.5	c.1612G>A	p.Asp538Asn	missense_variant	13/26	ENST00000331782.8	NP_002217.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAG2	ENST00000331782.8	c.1612G>A	p.Asp538Asn	missense_variant	13/26	1	NM_002226.5	ENSP00000328169.3
JAG2	ENST00000347004.2	c.1498G>A	p.Asp500Asn	missense_variant	12/25	1		ENSP00000328566.2

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15563 AN: 152182 Hom.: 996 Cov.: 30

Gnomad AFR AF: 0.0274

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.0895

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.104

GnomAD3 exomes AF: 0.137 AC: 33380 AN: 244132 Hom.: 2750 AF XY: 0.145 AC XY: 19318 AN XY: 132896

Gnomad AFR exome AF: 0.0235

Gnomad AMR exome AF: 0.115

Gnomad ASJ exome AF: 0.105

Gnomad EAS exome AF: 0.190

Gnomad SAS exome AF: 0.240

Gnomad FIN exome AF: 0.0917

Gnomad NFE exome AF: 0.134

Gnomad OTH exome AF: 0.137

GnomAD4 exome AF: 0.136 AC: 198139 AN: 1460228 Hom.: 14745 Cov.: 44 AF XY: 0.140 AC XY: 101827 AN XY: 726400

Gnomad4 AFR exome AF: 0.0232

Gnomad4 AMR exome AF: 0.118

Gnomad4 ASJ exome AF: 0.110

Gnomad4 EAS exome AF: 0.185

Gnomad4 SAS exome AF: 0.243

Gnomad4 FIN exome AF: 0.0911

Gnomad4 NFE exome AF: 0.132

Gnomad4 OTH exome AF: 0.132

GnomAD4 genome AF: 0.102 AC: 15570 AN: 152300 Hom.: 998 Cov.: 30 AF XY: 0.105 AC XY: 7791 AN XY: 74466

Gnomad4 AFR AF: 0.0273

Gnomad4 AMR AF: 0.127

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.182

Gnomad4 SAS AF: 0.215

Gnomad4 FIN AF: 0.0895

Gnomad4 NFE AF: 0.129

Gnomad4 OTH AF: 0.107

Alfa AF: 0.118 Hom.: 1099

Bravo AF: 0.101

TwinsUK AF: 0.131 AC: 486

ALSPAC AF: 0.137 AC: 528

ESP6500AA AF: 0.0325 AC: 143

ESP6500EA AF: 0.130 AC: 1119

ExAC AF: 0.137 AC: 16512

Asia WGS AF: 0.163 AC: 570 AN: 3476

EpiCase AF: 0.132

EpiControl AF: 0.132

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.74	D;.
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.85	D;D
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.23
Sift	Benign	0.26	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.20	B;B
Vest4		0.29
MPC		0.67
ClinPred		0.025	T
GERP RS		3.8
Varity_R		0.33
gMVP		0.60

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: rs9972231; hg19: chr14-105615648; COSMIC: COSV59306455; COSMIC: COSV59306455;