rs11145465

Variant names:

• chr9-69151677-C-A
• rs11145465
• ENST00000642889.1:c.353C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000642889.1(ENSG00000285130):​c.353C>A​(p.Ser118Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.204 in 1,231,738 control chromosomes in the GnomAD database, including 26,683 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.19 (2736 hom., cov: 31)
  • Exomes 𝑓: 0.21 (23947 hom.)
• Consequence: ENSG00000285130 ENST00000642889.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.46
• Publications: 30 publications found

Genes affected

ENSG00000285130 (HGNC:):

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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018132925).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000642889.1. 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_001369871.1		c.-222C>A		5_prime_UTR	Exon 2 of 25	NP_001356800.1
	TJP2	NM_001369870.1		c.-104C>A		5_prime_UTR	Exon 2 of 24	NP_001356799.1
	TJP2	NM_001170414.2		c.-104C>A		5_prime_UTR	Exon 2 of 22	NP_001163885.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000285130	ENST00000642889.1		c.353C>A	p.Ser118Tyr	missense	Exon 3 of 25	ENSP00000493780.1
	TJP2	ENST00000636438.1	TSL:5	c.143C>A	p.Ser48Tyr	missense	Exon 2 of 24	ENSP00000489860.1
	ENSG00000285130	ENST00000646862.1		c.572C>A	p.Ser191Tyr	missense	Exon 5 of 6	ENSP00000494599.1

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28403 AN: 151866 Hom.: 2736 Cov.: 31

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.327

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.00829

Gnomad SAS AF: 0.121

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.221

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.170

GnomAD4 exome AF: 0.206 AC: 222643 AN: 1079754 Hom.: 23947 Cov.: 31 AF XY: 0.207 AC XY: 105263 AN XY: 509744

African (AFR) AF: 0.182 AC: 4182 AN: 22966

American (AMR) AF: 0.132 AC: 1110 AN: 8416

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 3088 AN: 14388

East Asian (EAS) AF: 0.00422 AC: 112 AN: 26524

South Asian (SAS) AF: 0.133 AC: 2590 AN: 19492

European-Finnish (FIN) AF: 0.214 AC: 4609 AN: 21518

Middle Eastern (MID) AF: 0.195 AC: 569 AN: 2914

European-Non Finnish (NFE) AF: 0.215 AC: 197896 AN: 919872

Other (OTH) AF: 0.194 AC: 8487 AN: 43664

GnomAD4 genome AF: 0.187 AC: 28408 AN: 151984 Hom.: 2736 Cov.: 31 AF XY: 0.184 AC XY: 13650 AN XY: 74284

African (AFR) AF: 0.187 AC: 7737 AN: 41416

American (AMR) AF: 0.144 AC: 2196 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 711 AN: 3468

East Asian (EAS) AF: 0.00831 AC: 43 AN: 5172

South Asian (SAS) AF: 0.121 AC: 581 AN: 4810

European-Finnish (FIN) AF: 0.204 AC: 2156 AN: 10574

Middle Eastern (MID) AF: 0.228 AC: 66 AN: 290

European-Non Finnish (NFE) AF: 0.210 AC: 14264 AN: 67966

Other (OTH) AF: 0.169 AC: 356 AN: 2112

Alfa AF: 0.195 Hom.: 6819

Bravo AF: 0.184

TwinsUK AF: 0.227 AC: 841

ALSPAC AF: 0.209 AC: 805

Asia WGS AF: 0.0610 AC: 214 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Benign	0.83
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0018	T
PhyloP100		4.5
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=290/10	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11145465; hg19: chr9-71766593;