21-25683934-C-G

Variant names:

• chr21-25683934-C-G
• NM_021219.4:c.119C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_021219.4(JAM2):​c.119C>G​(p.Ala40Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,140 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A40V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: JAM2 NM_021219.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.80

Genes affected

JAM2 (HGNC:14686): (junctional adhesion molecule 2) This gene belongs to the immunoglobulin superfamily, and the junctional adhesion molecule (JAM) family. The protein encoded by this gene is a type I membrane protein that is localized at the tight junctions of both epithelial and endothelial cells. It acts as an adhesive ligand for interacting with a variety of immune cell types, and may play a role in lymphocyte homing to secondary lymphoid organs. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a topological_domain Extracellular (size 209) in uniprot entity JAM2_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_021219.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAM2	NM_021219.4	c.119C>G	p.Ala40Gly	missense_variant	Exon 2 of 10	ENST00000480456.6	NP_067042.1
JAM2	NM_001270408.2	c.119C>G	p.Ala40Gly	missense_variant	Exon 2 of 10		NP_001257337.1
JAM2	NM_001270407.2	c.119C>G	p.Ala40Gly	missense_variant	Exon 2 of 9		NP_001257336.1
JAM2	NR_072999.2	n.683C>G		non_coding_transcript_exon_variant	Exon 2 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAM2	ENST00000480456.6	c.119C>G	p.Ala40Gly	missense_variant	Exon 2 of 10	1	NM_021219.4	ENSP00000420419.1
JAM2	ENST00000400532.5	c.119C>G	p.Ala40Gly	missense_variant	Exon 2 of 10	1		ENSP00000383376.1
JAM2	ENST00000312957.9	c.119C>G	p.Ala40Gly	missense_variant	Exon 2 of 9	2		ENSP00000318416.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1452140 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 723086

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.06e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	.;T;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.5	M;M;M
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.029	D;D;T
Sift4G	Uncertain	0.051	T;T;T
Polyphen		0.96	.;D;.
Vest4		0.48
MutPred		0.57		Gain of catalytic residue at V41 (P = 0.1302);Gain of catalytic residue at V41 (P = 0.1302);Gain of catalytic residue at V41 (P = 0.1302);
MVP		0.81
MPC		0.67
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.23
gMVP		0.86

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: chr21-27056246;