21-25689968-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_021219.4(JAM2):c.236T>C(p.Leu79Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000269 in 1,596,182 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L79F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

JAM2
NM_021219.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.93

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 link	c.236T>C	p.Leu79Pro	missense_variant	Exon 3 of 10	ENST00000480456.6	NP_067042.1	P57087-1
JAM2	NM_001270408.2 link	c.236T>C	p.Leu79Pro	missense_variant	Exon 3 of 10		NP_001257337.1	P57087-3
JAM2	NM_001270407.2 link	c.134-3788T>C		intron_variant	Intron 2 of 8		NP_001257336.1	P57087-2
JAM2	NR_072999.2 link	n.800T>C		non_coding_transcript_exon_variant	Exon 3 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
JAM2	ENST00000480456.6 link	c.236T>C	p.Leu79Pro	missense_variant	Exon 3 of 10	1	NM_021219.4	ENSP00000420419.1	P57087-1
JAM2	ENST00000400532.5 link	c.236T>C	p.Leu79Pro	missense_variant	Exon 3 of 10	1		ENSP00000383376.1	P57087-3
JAM2	ENST00000312957.9 link	c.134-3788T>C		intron_variant	Intron 2 of 8	2		ENSP00000318416.6	P57087-2
JAM2	ENST00000460679.5 link	n.101T>C		non_coding_transcript_exon_variant	Exon 1 of 9	3		ENSP00000436801.1	H0YEX9

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000804

AC:

AN:

248836

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135112

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000291

AC:

AN:

1443964

Hom.:

Cov.:

AF XY:

0.0000278

AC XY:

AN XY:

719494

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:

0.0000383

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000335

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000828

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Nov 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.236T>C (p.L79P) alteration is located in exon 3 (coding exon 3) of the JAM2 gene. This alteration results from a T to C substitution at nucleotide position 236, causing the leucine (L) at amino acid position 79 to be replaced by a proline (P). 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

Uncertain

0.37

BayesDel_addAF

Benign

0.0053

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.30

.;T

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.69

T;T

M_CAP

Benign

0.057

MetaRNN

Uncertain

0.46

T;T

MetaSVM

Benign

-0.49

MutationAssessor

Benign

1.2

L;L

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-5.0

D;D

REVEL

Uncertain

0.38

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.016

D;D

Polyphen

1.0

.;D

Vest4

0.43

MVP

0.81

MPC

1.1

ClinPred

0.97

GERP RS

5.1

Varity_R

0.88

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over