chr21-25693777-A-C

Position:

• chr21-25693777-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_021219.4(JAM2):​c.263A>C​(p.Glu88Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: JAM2 NM_021219.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.75

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 4 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAM2	NM_021219.4	c.263A>C	p.Glu88Ala	missense_variant	4/10	ENST00000480456.6
JAM2	NM_001270408.2	c.263A>C	p.Glu88Ala	missense_variant	4/10
JAM2	NM_001270407.2	c.155A>C	p.Glu52Ala	missense_variant	3/9
JAM2	NR_072999.2	n.827A>C		non_coding_transcript_exon_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAM2	ENST00000480456.6	c.263A>C	p.Glu88Ala	missense_variant	4/10	1	NM_021219.4	P1
JAM2	ENST00000400532.5	c.263A>C	p.Glu88Ala	missense_variant	4/10	1
JAM2	ENST00000312957.9	c.155A>C	p.Glu52Ala	missense_variant	3/9	2
JAM2	ENST00000460679.5	c.131A>C	p.Glu44Ala	missense_variant, NMD_transcript_variant	2/9	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 26, 2023

The c.263A>C (p.E88A) alteration is located in exon 4 (coding exon 4) of the JAM2 gene. This alteration results from a A to C substitution at nucleotide position 263, causing the glutamic acid (E) at amino acid position 88 to be replaced by an alanine (A). 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	Benign	-0.040	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.2	L;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.3	D;D;.
REVEL	Benign	0.15
Sift	Benign	0.030	D;D;.
Sift4G	Benign	0.071	T;T;D
Polyphen		0.86	.;P;.
Vest4		0.57
MutPred		0.53		Gain of MoRF binding (P = 0.043);Gain of MoRF binding (P = 0.043);.;
MVP		0.57
MPC		0.72
ClinPred		0.95	D
GERP RS		5.6
Varity_R		0.24
gMVP		0.75

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.

Other links and lift over

hg19: chr21-27066089;