chr9-69248319-A-G

Variant names:

• chr9-69248319-A-G
• rs77236826
• ENST00000636247.1:n.3054A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The ENST00000636247.1(TJP2):​n.3054A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0778 in 1,484,356 control chromosomes in the GnomAD database, including 4,799 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.071 (432 hom., cov: 32)
  • Exomes 𝑓: 0.079 (4367 hom.)
• Consequence: TJP2 ENST00000636247.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.522
• Publications: 8 publications found

Genes affected

TJP2 (HGNC:11828): (tight junction protein 2) This gene encodes a zonula occluden that is a member of the membrane-associated guanylate kinase homolog family. The encoded protein functions as a component of the tight junction barrier in epithelial and endothelial cells and is necessary for proper assembly of tight junctions. Mutations in this gene have been identified in patients with hypercholanemia, and genomic duplication of a 270 kb region including this gene causes autosomal dominant deafness-51. Alternatively spliced transcripts encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

TJP2 Gene-Disease associations (from GenCC):

• cholestasis, progressive familial intrahepatic, 4

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet
• familial hypercholanemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hypercholanemia, familial 1

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000285130 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.018).
• BP6: Variant 9-69248319-A-G is Benign according to our data. Variant chr9-69248319-A-G is described in ClinVar as Benign. ClinVar VariationId is 44109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.081 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000636247.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TJP2	NM_004817.4	MANE Select	c.2880+95A>G		intron	N/A	NP_004808.2
	TJP2	NM_001170416.2		c.2973+95A>G		intron	N/A	NP_001163887.1
	TJP2	NM_001369875.1		c.2892+95A>G		intron	N/A	NP_001356804.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TJP2	ENST00000636247.1	TSL:1	n.3054A>G		non_coding_transcript_exon	Exon 19 of 19
	TJP2	ENST00000377245.9	TSL:1 MANE Select	c.2880+95A>G		intron	N/A	ENSP00000366453.4
	ENSG00000285130	ENST00000642889.1		c.3267+95A>G		intron	N/A	ENSP00000493780.1

Frequencies

GnomAD3 genomes AF: 0.0711 AC: 10824 AN: 152130 Hom.: 430 Cov.: 32

Gnomad AFR AF: 0.0559

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.0600

Gnomad ASJ AF: 0.0562

Gnomad EAS AF: 0.00598

Gnomad SAS AF: 0.0854

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0828

Gnomad OTH AF: 0.0771

GnomAD2 exomes AF: 0.0661 AC: 6723 AN: 101664 AF XY: 0.0687

Gnomad AFR exome AF: 0.0522

Gnomad AMR exome AF: 0.0421

Gnomad ASJ exome AF: 0.0601

Gnomad EAS exome AF: 0.00651

Gnomad FIN exome AF: 0.0900

Gnomad NFE exome AF: 0.0817

Gnomad OTH exome AF: 0.0642

GnomAD4 exome AF: 0.0786 AC: 104690 AN: 1332108 Hom.: 4367 Cov.: 33 AF XY: 0.0791 AC XY: 51273 AN XY: 648358

African (AFR) AF: 0.0558 AC: 1658 AN: 29688

American (AMR) AF: 0.0424 AC: 1155 AN: 27266

Ashkenazi Jewish (ASJ) AF: 0.0590 AC: 1217 AN: 20628

East Asian (EAS) AF: 0.00299 AC: 105 AN: 35090

South Asian (SAS) AF: 0.0884 AC: 5994 AN: 67784

European-Finnish (FIN) AF: 0.0929 AC: 4351 AN: 46820

Middle Eastern (MID) AF: 0.0828 AC: 444 AN: 5364

European-Non Finnish (NFE) AF: 0.0820 AC: 85662 AN: 1044482

Other (OTH) AF: 0.0746 AC: 4104 AN: 54986

GnomAD4 genome AF: 0.0712 AC: 10837 AN: 152248 Hom.: 432 Cov.: 32 AF XY: 0.0719 AC XY: 5350 AN XY: 74444

African (AFR) AF: 0.0560 AC: 2328 AN: 41558

American (AMR) AF: 0.0599 AC: 915 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0562 AC: 195 AN: 3472

East Asian (EAS) AF: 0.00580 AC: 30 AN: 5172

South Asian (SAS) AF: 0.0855 AC: 412 AN: 4818

European-Finnish (FIN) AF: 0.103 AC: 1089 AN: 10610

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0828 AC: 5632 AN: 68018

Other (OTH) AF: 0.0768 AC: 162 AN: 2110

Alfa AF: 0.0745 Hom.: 1497

Bravo AF: 0.0669

Asia WGS AF: 0.0430 AC: 151 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.42
DANN	Benign	0.23
PhyloP100		-0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs77236826; hg19: chr9-71863235; COSMIC: COSV55266203; COSMIC: COSV55266203;