chr21-25639822-A-G

Position:

• chr21-25639822-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_021219.4(JAM2):​c.1A>G​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: JAM2 NM_021219.4 start_lost
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.91

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-25639822-A-G is Pathogenic according to our data. Variant chr21-25639822-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 829533.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr21-25639822-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAM2	NM_021219.4	c.1A>G	p.Met1?	start_lost	1/10	ENST00000480456.6	NP_067042.1
JAM2	NM_001270408.2	c.1A>G	p.Met1?	start_lost	1/10		NP_001257337.1
JAM2	NM_001270407.2	c.1A>G	p.Met1?	start_lost	1/9		NP_001257336.1
JAM2	NR_072999.2	n.565A>G		non_coding_transcript_exon_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAM2	ENST00000480456.6	c.1A>G	p.Met1?	start_lost	1/10	1	NM_021219.4	ENSP00000420419	P1
JAM2	ENST00000400532.5	c.1A>G	p.Met1?	start_lost	1/10	1		ENSP00000383376
JAM2	ENST00000312957.9	c.1A>G	p.Met1?	start_lost	1/9	2		ENSP00000318416

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Basal ganglia calcification, idiopathic, 8, autosomal recessive Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 27, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.0077	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.057	.;T;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.31	N
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Benign	-0.77	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.29
Sift	Uncertain	0.019	D;D;D
Sift4G	Uncertain	0.037	D;T;T
Polyphen		0.71	.;P;.
Vest4		0.78
MutPred		0.87		Loss of catalytic residue at M1 (P = 0.1287);Loss of catalytic residue at M1 (P = 0.1287);Loss of catalytic residue at M1 (P = 0.1287);
MVP		0.54
ClinPred		0.98	D
GERP RS		3.9
Varity_R		0.26
gMVP		0.73

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

Other links and lift over

dbSNP: rs1600978441; hg19: chr21-27012134;