9-69205232-G-A

Variant names:

• chr9-69205232-G-A
• rs4493966
• NM_004817.4:c.61-7316G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004817.4(TJP2):​c.61-7316G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0429 in 1,537,142 control chromosomes in the GnomAD database, including 2,525 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (347 hom., cov: 33)
  • Exomes 𝑓: 0.043 (2178 hom.)
• Consequence: TJP2 NM_004817.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.142
• 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.739829E-4).
• BP6: Variant 9-69205232-G-A is Benign according to our data. Variant chr9-69205232-G-A is described in ClinVar as Benign. ClinVar VariationId is 44104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TJP2	NM_004817.4	c.61-7316G>A		intron_variant	Intron 1 of 22	ENST00000377245.9	NP_004808.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TJP2	ENST00000377245.9	c.61-7316G>A		intron_variant	Intron 1 of 22	1	NM_004817.4	ENSP00000366453.4
ENSG00000285130	ENST00000642889.1	c.448-7316G>A		intron_variant	Intron 3 of 24			ENSP00000493780.1

Frequencies

GnomAD3 genomes AF: 0.0436 AC: 6639 AN: 152174 Hom.: 340 Cov.: 33

Gnomad AFR AF: 0.0114

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.0334

Gnomad EAS AF: 0.0541

Gnomad SAS AF: 0.0429

Gnomad FIN AF: 0.0271

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0374

Gnomad OTH AF: 0.0574

GnomAD2 exomes AF: 0.0738 AC: 10289 AN: 139454 AF XY: 0.0665

Gnomad AFR exome AF: 0.00895

Gnomad AMR exome AF: 0.242

Gnomad ASJ exome AF: 0.0358

Gnomad EAS exome AF: 0.0492

Gnomad FIN exome AF: 0.0298

Gnomad NFE exome AF: 0.0380

Gnomad OTH exome AF: 0.0597

GnomAD4 exome AF: 0.0428 AC: 59259 AN: 1384850 Hom.: 2178 Cov.: 33 AF XY: 0.0423 AC XY: 28896 AN XY: 683356

African (AFR) AF: 0.00798 AC: 252 AN: 31594

American (AMR) AF: 0.237 AC: 8460 AN: 35686

Ashkenazi Jewish (ASJ) AF: 0.0336 AC: 847 AN: 25180

East Asian (EAS) AF: 0.0439 AC: 1569 AN: 35732

South Asian (SAS) AF: 0.0403 AC: 3189 AN: 79220

European-Finnish (FIN) AF: 0.0289 AC: 1010 AN: 35002

Middle Eastern (MID) AF: 0.0228 AC: 130 AN: 5696

European-Non Finnish (NFE) AF: 0.0382 AC: 41254 AN: 1078826

Other (OTH) AF: 0.0440 AC: 2548 AN: 57914

GnomAD4 genome AF: 0.0437 AC: 6651 AN: 152292 Hom.: 347 Cov.: 33 AF XY: 0.0449 AC XY: 3344 AN XY: 74466

African (AFR) AF: 0.0114 AC: 474 AN: 41570

American (AMR) AF: 0.167 AC: 2554 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0334 AC: 116 AN: 3472

East Asian (EAS) AF: 0.0535 AC: 277 AN: 5180

South Asian (SAS) AF: 0.0423 AC: 204 AN: 4824

European-Finnish (FIN) AF: 0.0271 AC: 288 AN: 10608

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0374 AC: 2545 AN: 68032

Other (OTH) AF: 0.0591 AC: 125 AN: 2114

Alfa AF: 0.0401 Hom.: 453

Bravo AF: 0.0553

TwinsUK AF: 0.0364 AC: 135

ALSPAC AF: 0.0361 AC: 139

ESP6500AA AF: 0.0166 AC: 23

ESP6500EA AF: 0.0371 AC: 118

ExAC AF: 0.0330 AC: 708

Asia WGS AF: 0.0560 AC: 194 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Feb 07, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arg24His in Exon 01D of TJP2: This variant is not expected to have clinical sign ificance because it has been identified in 3.7% (118/3182) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs4493966). -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.1
DANN	Benign	0.80
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0039	N
LIST_S2	Benign	0.22	T;T;T;T
MetaRNN	Benign	0.00087	T;T;T;T
MetaSVM	Benign	-0.95	T
PhyloP100		0.14
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.72	N;.;N;.
REVEL	Benign	0.028
Sift	Benign	0.29	T;.;T;.
Sift4G	Benign	0.24	T;.;T;.
Vest4		0.10
MPC		0.24
ClinPred		0.0013	T
GERP RS		-2.6
PromoterAI		-0.098	Neutral
gMVP		0.17
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs4493966; hg19: chr9-71820148; COSMIC: COSV55264360;