21-25693774-C-G

Variant names:

• chr21-25693774-C-G
• NM_021219.4:c.260C>G

Variant summary

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

The NM_021219.4(JAM2):​c.260C>G​(p.Ala87Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,374 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: JAM2 NM_021219.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.85

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 2 ACMG points.

• 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.260C>G	p.Ala87Gly	missense_variant	Exon 4 of 10	ENST00000480456.6	NP_067042.1
JAM2	NM_001270408.2	c.260C>G	p.Ala87Gly	missense_variant	Exon 4 of 10		NP_001257337.1
JAM2	NM_001270407.2	c.152C>G	p.Ala51Gly	missense_variant	Exon 3 of 9		NP_001257336.1
JAM2	NR_072999.2	n.824C>G		non_coding_transcript_exon_variant	Exon 4 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAM2	ENST00000480456.6	c.260C>G	p.Ala87Gly	missense_variant	Exon 4 of 10	1	NM_021219.4	ENSP00000420419.1
JAM2	ENST00000400532.5	c.260C>G	p.Ala87Gly	missense_variant	Exon 4 of 10	1		ENSP00000383376.1
JAM2	ENST00000312957.9	c.152C>G	p.Ala51Gly	missense_variant	Exon 3 of 9	2		ENSP00000318416.6
JAM2	ENST00000460679.5	n.125C>G		non_coding_transcript_exon_variant	Exon 2 of 9	3		ENSP00000436801.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461374 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727006

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.260C>G (p.A87G) alteration is located in exon 4 (coding exon 4) of the JAM2 gene. This alteration results from a C to G substitution at nucleotide position 260, causing the alanine (A) at amino acid position 87 to be replaced by a glycine (G). 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	0.27
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	.;T;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.079	D
MetaRNN	Uncertain	0.62	D;D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.8	M;M;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.6	D;D;.
REVEL	Uncertain	0.35
Sift	Uncertain	0.0060	D;D;.
Sift4G	Uncertain	0.049	D;T;D
Polyphen		1.0	.;D;.
Vest4		0.57
MutPred		0.52		Loss of stability (P = 0.0567);Loss of stability (P = 0.0567);.;
MVP		0.86
MPC		0.85
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.67
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: chr21-27066086;