21-25698683-C-T

Variant names:

• chr21-25698683-C-T
• rs749679149
• NM_021219.4:c.401C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_021219.4(JAM2):​c.401C>T​(p.Pro134Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: JAM2 NM_021219.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.25
• Publications: 0 publications found

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]

JAM2 Gene-Disease associations (from GenCC):

• basal ganglia calcification, idiopathic, 8, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• bilateral striopallidodentate calcinosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LOC124905002 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021219.4. 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
	JAM2	NM_021219.4	MANE Select	c.401C>T	p.Pro134Leu	missense	Exon 5 of 10	NP_067042.1	P57087-1
	JAM2	NM_001270408.2		c.401C>T	p.Pro134Leu	missense	Exon 5 of 10	NP_001257337.1	P57087-3
	JAM2	NM_001270407.2		c.293C>T	p.Pro98Leu	missense	Exon 4 of 9	NP_001257336.1	P57087-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAM2	ENST00000480456.6	TSL:1 MANE Select	c.401C>T	p.Pro134Leu	missense	Exon 5 of 10	ENSP00000420419.1	P57087-1
	JAM2	ENST00000400532.5	TSL:1	c.401C>T	p.Pro134Leu	missense	Exon 5 of 10	ENSP00000383376.1	P57087-3
	JAM2	ENST00000948521.1		c.446C>T	p.Pro149Leu	missense	Exon 6 of 11	ENSP00000618580.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248904 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461204 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726884

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111484

Other (OTH) AF: 0.00 AC: 0 AN: 60378

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Benign	0.0052	T
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-8.7	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.71		Loss of disorder (P = 0.0276)
MVP		0.90
MPC		0.86
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.68
gMVP		0.89
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs749679149; hg19: chr21-27070995;