14-105149311-C-T

Variant names:

• chr14-105149311-C-T
• rs9972231
• NM_002226.5:c.1612G>A

Variant summary

Our verdict is Benign. The variant received -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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 36 publications found

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 Gene-Disease associations (from GenCC):

• muscular dystrophy, limb-girdle, autosomal recessive 27

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002226.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAG2	NM_002226.5	MANE Select	c.1612G>A	p.Asp538Asn	missense	Exon 13 of 26	NP_002217.3
	JAG2	NM_145159.3		c.1498G>A	p.Asp500Asn	missense	Exon 12 of 25	NP_660142.1	Q9Y219-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAG2	ENST00000331782.8	TSL:1 MANE Select	c.1612G>A	p.Asp538Asn	missense	Exon 13 of 26	ENSP00000328169.3	Q9Y219-1
	JAG2	ENST00000347004.2	TSL:1	c.1498G>A	p.Asp500Asn	missense	Exon 12 of 25	ENSP00000328566.2	Q9Y219-2
	JAG2	ENST00000938643.1		c.1615G>A	p.Asp539Asn	missense	Exon 13 of 26	ENSP00000608702.1

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

GnomAD2 exomes AF: 0.137 AC: 33380 AN: 244132 AF XY: 0.145

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 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

African (AFR) AF: 0.0232 AC: 775 AN: 33476

American (AMR) AF: 0.118 AC: 5272 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 2865 AN: 26128

East Asian (EAS) AF: 0.185 AC: 7360 AN: 39694

South Asian (SAS) AF: 0.243 AC: 20935 AN: 86246

European-Finnish (FIN) AF: 0.0911 AC: 4728 AN: 51920

Middle Eastern (MID) AF: 0.175 AC: 1007 AN: 5758

European-Non Finnish (NFE) AF: 0.132 AC: 147250 AN: 1111916

Other (OTH) AF: 0.132 AC: 7947 AN: 60370

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

African (AFR) AF: 0.0273 AC: 1137 AN: 41576

American (AMR) AF: 0.127 AC: 1948 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 380 AN: 3472

East Asian (EAS) AF: 0.182 AC: 944 AN: 5176

South Asian (SAS) AF: 0.215 AC: 1039 AN: 4828

European-Finnish (FIN) AF: 0.0895 AC: 950 AN: 10616

Middle Eastern (MID) AF: 0.140 AC: 41 AN: 292

European-Non Finnish (NFE) AF: 0.129 AC: 8753 AN: 68004

Other (OTH) AF: 0.107 AC: 226 AN: 2116

Alfa AF: 0.122 Hom.: 1821

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 v4.9

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
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.3
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.23
Sift	Benign	0.26	T
Sift4G	Benign	0.24	T
Polyphen		0.20	B
Vest4		0.29
MPC		0.67
ClinPred		0.025	T
GERP RS		3.8
Varity_R		0.33
gMVP		0.60
Mutation Taster		=81/19	polymorphism (auto)

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

Other links and lift over

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