rs11788754

Variant names:

• chr9-69246769-G-A
• rs11788754
• NM_004817.4:c.2646G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-69246769-G-A
• chr9-69246769-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004817.4(TJP2):​c.2646G>A​(p.Ala882Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0175 in 1,614,012 control chromosomes in the GnomAD database, including 304 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (21 hom., cov: 32)
  • Exomes 𝑓: 0.018 (283 hom.)
• Consequence: TJP2 NM_004817.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.342
• Publications: 5 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=-0.38).
• BP6: Variant 9-69246769-G-A is Benign according to our data. Variant chr9-69246769-G-A is described in ClinVar as Benign. ClinVar VariationId is 44098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.342 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0133 (2018/152254) while in subpopulation NFE AF = 0.0212 (1439/68030). AF 95% confidence interval is 0.0202. There are 21 homozygotes in GnomAd4. There are 932 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AD,AR,Unknown gene

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.2646G>A	p.Ala882Ala	synonymous	Exon 18 of 23	NP_004808.2
	TJP2	NM_001170416.2		c.2739G>A	p.Ala913Ala	synonymous	Exon 18 of 23	NP_001163887.1	Q9UDY2-7
	TJP2	NM_001369875.1		c.2658G>A	p.Ala886Ala	synonymous	Exon 18 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.2646G>A	p.Ala882Ala	synonymous	Exon 18 of 23	ENSP00000366453.4	Q9UDY2-1
	ENSG00000285130	ENST00000642889.1		c.3033G>A	p.Ala1011Ala	synonymous	Exon 20 of 25	ENSP00000493780.1	A0A2R8YDH4
	TJP2	ENST00000348208.9	TSL:1	c.2646G>A	p.Ala882Ala	synonymous	Exon 18 of 21	ENSP00000345893.4	Q9UDY2-2

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2018 AN: 152136 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.00348

Gnomad AMI AF: 0.00879

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0184

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0211

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0141 AC: 3534 AN: 251458 AF XY: 0.0152

Gnomad AFR exome AF: 0.00302

Gnomad AMR exome AF: 0.00726

Gnomad ASJ exome AF: 0.0150

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00240

Gnomad NFE exome AF: 0.0203

Gnomad OTH exome AF: 0.0164

GnomAD4 exome AF: 0.0180 AC: 26248 AN: 1461758 Hom.: 283 Cov.: 31 AF XY: 0.0181 AC XY: 13170 AN XY: 727186

African (AFR) AF: 0.00367 AC: 123 AN: 33478

American (AMR) AF: 0.00724 AC: 324 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 353 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.0192 AC: 1652 AN: 86258

European-Finnish (FIN) AF: 0.00322 AC: 172 AN: 53418

Middle Eastern (MID) AF: 0.0248 AC: 143 AN: 5768

European-Non Finnish (NFE) AF: 0.0203 AC: 22586 AN: 1111900

Other (OTH) AF: 0.0148 AC: 894 AN: 60392

GnomAD4 genome AF: 0.0133 AC: 2018 AN: 152254 Hom.: 21 Cov.: 32 AF XY: 0.0125 AC XY: 932 AN XY: 74438

African (AFR) AF: 0.00347 AC: 144 AN: 41542

American (AMR) AF: 0.0147 AC: 224 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.0182 AC: 88 AN: 4822

European-Finnish (FIN) AF: 0.00217 AC: 23 AN: 10610

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0212 AC: 1439 AN: 68030

Other (OTH) AF: 0.0123 AC: 26 AN: 2112

Alfa AF: 0.0174 Hom.: 23

Bravo AF: 0.0132

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0221

EpiControl AF: 0.0229

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	7.1
DANN	Benign	0.60
PhyloP100		-0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs11788754; hg19: chr9-71861685; COSMIC: COSV55266873;