dbSNP rs754402473: JAM2:p.Ala40Glu (chr21-25683934-C-A) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_021219.4(JAM2):c.119C>A(p.Ala40Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

JAM2
NM_021219.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.80

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 Uncertain_significance. Variant got 5 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;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.82

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAM2	NM_021219.4 link	c.119C>A	p.Ala40Glu	missense_variant	Exon 2 of 10	ENST00000480456.6	NP_067042.1	P57087-1
JAM2	NM_001270408.2 link	c.119C>A	p.Ala40Glu	missense_variant	Exon 2 of 10		NP_001257337.1	P57087-3
JAM2	NM_001270407.2 link	c.119C>A	p.Ala40Glu	missense_variant	Exon 2 of 9		NP_001257336.1	P57087-2
JAM2	NR_072999.2 link	n.683C>A		non_coding_transcript_exon_variant	Exon 2 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
JAM2	ENST00000480456.6 link	c.119C>A	p.Ala40Glu	missense_variant	Exon 2 of 10	1	NM_021219.4	ENSP00000420419.1	P57087-1
JAM2	ENST00000400532.5 link	c.119C>A	p.Ala40Glu	missense_variant	Exon 2 of 10	1		ENSP00000383376.1	P57087-3
JAM2	ENST00000312957.9 link	c.119C>A	p.Ala40Glu	missense_variant	Exon 2 of 9	2		ENSP00000318416.6	P57087-2

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

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1452138

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74376

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

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

.;T;.

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.77

T;T;T

M_CAP

Benign

0.076

MetaRNN

Pathogenic

0.82

D;D;D

MetaSVM

Uncertain

-0.059

MutationAssessor

Uncertain

2.2

M;M;M

PrimateAI

Benign

0.44

PROVEAN

Benign

-2.3

N;N;N

REVEL

Uncertain

0.37

Sift

Uncertain

0.011

D;D;D

Sift4G

Uncertain

0.028

D;D;T

Polyphen

0.99

.;D;.

Vest4

0.70

MutPred

0.77

Gain of disorder (P = 0.0562);Gain of disorder (P = 0.0562);Gain of disorder (P = 0.0562);

MVP

0.86

MPC

0.86

ClinPred

0.96

GERP RS

4.7

Varity_R

0.28

gMVP

0.96

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over