Variant chr21-25693837-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_021219.4(JAM2):c.323G>T(p.Arg108Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,740 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R108H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

JAM2
NM_021219.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.17

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a topological_domain Extracellular (size 209) in uniprot entity JAM2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_021219.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr21-25693837-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 829539.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
JAM2	NM_021219.4 linkuse as main transcript	c.323G>T	p.Arg108Leu	missense_variant	4/10	ENST00000480456.6
JAM2	NM_001270408.2 linkuse as main transcript	c.323G>T	p.Arg108Leu	missense_variant	4/10
JAM2	NM_001270407.2 linkuse as main transcript	c.215G>T	p.Arg72Leu	missense_variant	3/9
JAM2	NR_072999.2 linkuse as main transcript	n.887G>T		non_coding_transcript_exon_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAM2	ENST00000480456.6 linkuse as main transcript	c.323G>T	p.Arg108Leu	missense_variant	4/10	1	NM_021219.4	P1	P57087-1
JAM2	ENST00000400532.5 linkuse as main transcript	c.323G>T	p.Arg108Leu	missense_variant	4/10	1			P57087-3
JAM2	ENST00000312957.9 linkuse as main transcript	c.215G>T	p.Arg72Leu	missense_variant	3/9	2			P57087-2
JAM2	ENST00000460679.5 linkuse as main transcript	c.191G>T	p.Arg64Leu	missense_variant, NMD_transcript_variant	2/9	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461740

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727190

show subpopulations

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2024

The c.323G>T (p.R108L) alteration is located in exon 4 (coding exon 4) of the JAM2 gene. This alteration results from a G to T substitution at nucleotide position 323, causing the arginine (R) at amino acid position 108 to be replaced by a leucine (L). 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

0.33

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.86

D;D;D

MetaSVM

Uncertain

-0.22

MutationAssessor

Uncertain

2.2

M;M;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-5.1

D;D;.

REVEL

Uncertain

0.47

Sift

Uncertain

0.0020

D;D;.

Sift4G

Uncertain

0.019

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.83

MutPred

0.50

Loss of MoRF binding (P = 0.0316);Loss of MoRF binding (P = 0.0316);.;

MVP

0.91

MPC

0.95

ClinPred

0.99

GERP RS

5.6

Varity_R

0.84

gMVP

0.92

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over