21-25639776-C-A

Variant names:

• chr21-25639776-C-A
• rs118115569
• NM_021219.4:c.-46C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021219.4(JAM2):​c.-46C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0549 in 1,425,876 control chromosomes in the GnomAD database, including 2,382 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (247 hom., cov: 32)
  • Exomes 𝑓: 0.055 (2135 hom.)
• Consequence: JAM2 NM_021219.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.454
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• basal ganglia calcification, idiopathic, 8, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• bilateral striopallidodentate calcinosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 21-25639776-C-A is Benign according to our data. Variant chr21-25639776-C-A is described in ClinVar as Benign. ClinVar VariationId is 1258951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0584 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021219.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAM2	NM_021219.4	MANE Select	c.-46C>A		5_prime_UTR	Exon 1 of 10	NP_067042.1	P57087-1
	JAM2	NM_001270408.2		c.-46C>A		5_prime_UTR	Exon 1 of 10	NP_001257337.1	P57087-3
	JAM2	NM_001270407.2		c.-46C>A		5_prime_UTR	Exon 1 of 9	NP_001257336.1	P57087-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAM2	ENST00000480456.6	TSL:1 MANE Select	c.-46C>A		5_prime_UTR	Exon 1 of 10	ENSP00000420419.1	P57087-1
	JAM2	ENST00000400532.5	TSL:1	c.-46C>A		5_prime_UTR	Exon 1 of 10	ENSP00000383376.1	P57087-3
	JAM2	ENST00000948521.1		c.-46C>A		5_prime_UTR	Exon 1 of 11	ENSP00000618580.1

Frequencies

GnomAD3 genomes AF: 0.0544 AC: 8275 AN: 152068 Hom.: 246 Cov.: 32

Gnomad AFR AF: 0.0526

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0617

Gnomad ASJ AF: 0.0785

Gnomad EAS AF: 0.00871

Gnomad SAS AF: 0.0354

Gnomad FIN AF: 0.0523

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0581

Gnomad OTH AF: 0.0517

GnomAD2 exomes AF: 0.0560 AC: 7734 AN: 138168 AF XY: 0.0549

Gnomad AFR exome AF: 0.0488

Gnomad AMR exome AF: 0.0872

Gnomad ASJ exome AF: 0.0826

Gnomad EAS exome AF: 0.00439

Gnomad FIN exome AF: 0.0547

Gnomad NFE exome AF: 0.0582

Gnomad OTH exome AF: 0.0564

GnomAD4 exome AF: 0.0549 AC: 69976 AN: 1273692 Hom.: 2135 Cov.: 18 AF XY: 0.0542 AC XY: 34339 AN XY: 633646

African (AFR) AF: 0.0490 AC: 1408 AN: 28736

American (AMR) AF: 0.0827 AC: 2791 AN: 33732

Ashkenazi Jewish (ASJ) AF: 0.0781 AC: 1846 AN: 23630

East Asian (EAS) AF: 0.0226 AC: 792 AN: 34972

South Asian (SAS) AF: 0.0366 AC: 2759 AN: 75416

European-Finnish (FIN) AF: 0.0527 AC: 2016 AN: 38234

Middle Eastern (MID) AF: 0.0509 AC: 245 AN: 4810

European-Non Finnish (NFE) AF: 0.0566 AC: 55447 AN: 980448

Other (OTH) AF: 0.0497 AC: 2672 AN: 53714

GnomAD4 genome AF: 0.0544 AC: 8279 AN: 152184 Hom.: 247 Cov.: 32 AF XY: 0.0549 AC XY: 4084 AN XY: 74404

African (AFR) AF: 0.0525 AC: 2181 AN: 41546

American (AMR) AF: 0.0617 AC: 943 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0785 AC: 272 AN: 3466

East Asian (EAS) AF: 0.00873 AC: 45 AN: 5152

South Asian (SAS) AF: 0.0363 AC: 175 AN: 4824

European-Finnish (FIN) AF: 0.0523 AC: 554 AN: 10600

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0581 AC: 3952 AN: 67986

Other (OTH) AF: 0.0531 AC: 112 AN: 2108

Alfa AF: 0.0552 Hom.: 47

Bravo AF: 0.0555

Asia WGS AF: 0.0400 AC: 142 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	13
DANN	Benign	0.84
PhyloP100		0.45
PromoterAI		-0.038	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs118115569; hg19: chr21-27012088;