rs2095876

Variant names:

• chr9-69248071-G-A
• rs2095876
• NM_004817.4:c.2727G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-69248071-G-A
• chr9-69248071-G-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004817.4(TJP2):​c.2727G>A​(p.Ala909Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 1,613,750 control chromosomes in the GnomAD database, including 45,455 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4418 hom., cov: 32)
  • Exomes 𝑓: 0.23 (41037 hom.)
• Consequence: TJP2 NM_004817.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.156
• Publications: 23 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: PanelApp Australia, 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: AR, Unknown Classification: LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

ENSG00000285130 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 9-69248071-G-A is Benign according to our data. Variant chr9-69248071-G-A is described in ClinVar as Benign. ClinVar VariationId is 44106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.156 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.425 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004817.4. 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
	TJP2	NM_004817.4	MANE Select	c.2727G>A	p.Ala909Ala	synonymous	Exon 19 of 23	NP_004808.2
	TJP2	NM_001170416.2		c.2820G>A	p.Ala940Ala	synonymous	Exon 19 of 23	NP_001163887.1	Q9UDY2-7
	TJP2	NM_001369875.1		c.2739G>A	p.Ala913Ala	synonymous	Exon 19 of 23	NP_001356804.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TJP2	ENST00000377245.9	TSL:1 MANE Select	c.2727G>A	p.Ala909Ala	synonymous	Exon 19 of 23	ENSP00000366453.4	Q9UDY2-1
	ENSG00000285130	ENST00000642889.1		c.3114G>A	p.Ala1038Ala	synonymous	Exon 21 of 25	ENSP00000493780.1	A0A2R8YDH4
	TJP2	ENST00000348208.9	TSL:1	c.2727G>A	p.Ala909Ala	synonymous	Exon 19 of 21	ENSP00000345893.4	Q9UDY2-2

Frequencies

GnomAD3 genomes AF: 0.230 AC: 34889 AN: 151964 Hom.: 4411 Cov.: 32

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.374

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.441

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.236

GnomAD2 exomes AF: 0.271 AC: 68033 AN: 251108 AF XY: 0.258

Gnomad AFR exome AF: 0.181

Gnomad AMR exome AF: 0.536

Gnomad ASJ exome AF: 0.163

Gnomad EAS exome AF: 0.435

Gnomad FIN exome AF: 0.234

Gnomad NFE exome AF: 0.215

Gnomad OTH exome AF: 0.242

GnomAD4 exome AF: 0.226 AC: 330387 AN: 1461668 Hom.: 41037 Cov.: 37 AF XY: 0.224 AC XY: 162619 AN XY: 727120

African (AFR) AF: 0.174 AC: 5810 AN: 33474

American (AMR) AF: 0.516 AC: 23061 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 4252 AN: 26130

East Asian (EAS) AF: 0.434 AC: 17218 AN: 39696

South Asian (SAS) AF: 0.193 AC: 16633 AN: 86242

European-Finnish (FIN) AF: 0.226 AC: 12084 AN: 53390

Middle Eastern (MID) AF: 0.159 AC: 914 AN: 5760

European-Non Finnish (NFE) AF: 0.213 AC: 237065 AN: 1111874

Other (OTH) AF: 0.221 AC: 13350 AN: 60384

GnomAD4 genome AF: 0.230 AC: 34915 AN: 152082 Hom.: 4418 Cov.: 32 AF XY: 0.232 AC XY: 17261 AN XY: 74358

African (AFR) AF: 0.181 AC: 7525 AN: 41504

American (AMR) AF: 0.374 AC: 5722 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 578 AN: 3468

East Asian (EAS) AF: 0.440 AC: 2264 AN: 5140

South Asian (SAS) AF: 0.215 AC: 1035 AN: 4816

European-Finnish (FIN) AF: 0.231 AC: 2441 AN: 10588

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.213 AC: 14471 AN: 67966

Other (OTH) AF: 0.239 AC: 505 AN: 2110

Alfa AF: 0.198 Hom.: 1989

Bravo AF: 0.244

Asia WGS AF: 0.310 AC: 1077 AN: 3478

EpiCase AF: 0.207

EpiControl AF: 0.207

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Cholestasis, progressive familial intrahepatic, 4 (1)
-	-	1	Hypercholanemia, familial 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	13
DANN	Benign	0.80
PhyloP100		0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
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: rs2095876; hg19: chr9-71862987; COSMIC: COSV55264507;