chr21-25639842-C-A

Position:

• chr21-25639842-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021219.4(JAM2):​c.21C>A​(p.His7Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00317 in 1,590,384 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (66 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (59 hom.)
• Consequence: JAM2 NM_021219.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.42

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020769238).
• BP6: Variant 21-25639842-C-A is Benign according to our data. Variant chr21-25639842-C-A is described in ClinVar as [Benign]. Clinvar id is 1276642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0569 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAM2	NM_021219.4	c.21C>A	p.His7Gln	missense_variant	1/10	ENST00000480456.6
JAM2	NM_001270408.2	c.21C>A	p.His7Gln	missense_variant	1/10
JAM2	NM_001270407.2	c.21C>A	p.His7Gln	missense_variant	1/9
JAM2	NR_072999.2	n.585C>A		non_coding_transcript_exon_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAM2	ENST00000480456.6	c.21C>A	p.His7Gln	missense_variant	1/10	1	NM_021219.4	P1
JAM2	ENST00000400532.5	c.21C>A	p.His7Gln	missense_variant	1/10	1
JAM2	ENST00000312957.9	c.21C>A	p.His7Gln	missense_variant	1/9	2

Frequencies

GnomAD3 genomes AF: 0.0170 AC: 2578 AN: 151890 Hom.: 66 Cov.: 32

Gnomad AFR AF: 0.0590

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00694

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00817

GnomAD3 exomes AF: 0.00385 AC: 800 AN: 207972 Hom.: 21 AF XY: 0.00293 AC XY: 331 AN XY: 113000

Gnomad AFR exome AF: 0.0585

Gnomad AMR exome AF: 0.00219

Gnomad ASJ exome AF: 0.000868

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000380

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000650

Gnomad OTH exome AF: 0.000774

GnomAD4 exome AF: 0.00171 AC: 2453 AN: 1438374 Hom.: 59 Cov.: 30 AF XY: 0.00142 AC XY: 1010 AN XY: 713582

Gnomad4 AFR exome AF: 0.0598

Gnomad4 AMR exome AF: 0.00259

Gnomad4 ASJ exome AF: 0.000820

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000170

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000508

Gnomad4 OTH exome AF: 0.00442

GnomAD4 genome AF: 0.0170 AC: 2581 AN: 152010 Hom.: 66 Cov.: 32 AF XY: 0.0160 AC XY: 1189 AN XY: 74318

Gnomad4 AFR AF: 0.0589

Gnomad4 AMR AF: 0.00693

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00807

Alfa AF: 0.00428 Hom.: 15

Bravo AF: 0.0190

ESP6500AA AF: 0.0454 AC: 179

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.00429 AC: 514

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.029	.;T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.38	T;T;T
MetaRNN	Benign	0.0021	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N;N
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.69	N;N;N
REVEL	Benign	0.035
Sift	Benign	0.44	T;T;T
Sift4G	Benign	0.23	T;T;T
Polyphen		0.0020	.;B;.
Vest4		0.17
MutPred		0.40		Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);
MVP		0.48
MPC		0.23
ClinPred		0.019	T
GERP RS		3.2
Varity_R		0.057
gMVP		0.56

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: rs8132639; hg19: chr21-27012154;