14-105142874-C-T

Position:

• chr14-105142874-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002226.5(JAG2):​c.3538G>A​(p.Asp1180Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: JAG2 NM_002226.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.61

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24218825).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAG2	NM_002226.5	c.3538G>A	p.Asp1180Asn	missense_variant	26/26	ENST00000331782.8
JAG2	NM_145159.3	c.3424G>A	p.Asp1142Asn	missense_variant	25/25
JAG2	XM_047431352.1	c.3196G>A	p.Asp1066Asn	missense_variant	25/25
JAG2	XM_047431353.1	c.3082G>A	p.Asp1028Asn	missense_variant	24/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAG2	ENST00000331782.8	c.3538G>A	p.Asp1180Asn	missense_variant	26/26	1	NM_002226.5	P1
JAG2	ENST00000347004.2	c.3424G>A	p.Asp1142Asn	missense_variant	25/25	1
JAG2	ENST00000546616.1	n.1156G>A		non_coding_transcript_exon_variant	7/7	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2022

The c.3538G>A (p.D1180N) alteration is located in exon 26 (coding exon 26) of the JAG2 gene. This alteration results from a G to A substitution at nucleotide position 3538, causing the aspartic acid (D) at amino acid position 1180 to be replaced by an asparagine (N). 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	0.090
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T;T
M_CAP	Pathogenic	0.51	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Uncertain	0.081	D
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	0.64	N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.28
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		0.55	P;P
Vest4		0.14
MutPred		0.089		Gain of loop (P = 0.0195);.;
MVP		0.76
MPC		0.49
ClinPred		0.83	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.052

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-105609211;