rs34774441

Variant names:

• chr9-69236961-G-A
• rs34774441
• NM_004817.4:c.2004G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-69236961-G-A
• chr9-69236961-G-C

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.2004G>A​(p.Met668Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0592 in 1,614,088 control chromosomes in the GnomAD database, including 3,222 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (201 hom., cov: 32)
  • Exomes 𝑓: 0.061 (3021 hom.)
• Consequence: TJP2 NM_004817.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 6.96
• Publications: 18 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020027757).
• BP6: Variant 9-69236961-G-A is Benign according to our data. Variant chr9-69236961-G-A is described in ClinVar as Benign. ClinVar VariationId is 44095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0726 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.2004G>A	p.Met668Ile	missense	Exon 14 of 23	NP_004808.2
	TJP2	NM_001170416.2		c.2097G>A	p.Met699Ile	missense	Exon 14 of 23	NP_001163887.1	Q9UDY2-7
	TJP2	NM_001369875.1		c.2016G>A	p.Met672Ile	missense	Exon 14 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.2004G>A	p.Met668Ile	missense	Exon 14 of 23	ENSP00000366453.4	Q9UDY2-1
	ENSG00000285130	ENST00000642889.1		c.2391G>A	p.Met797Ile	missense	Exon 16 of 25	ENSP00000493780.1	A0A2R8YDH4
	TJP2	ENST00000348208.9	TSL:1	c.2004G>A	p.Met668Ile	missense	Exon 14 of 21	ENSP00000345893.4	Q9UDY2-2

Frequencies

GnomAD3 genomes AF: 0.0470 AC: 7156 AN: 152176 Hom.: 201 Cov.: 32

Gnomad AFR AF: 0.0199

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0423

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0788

Gnomad FIN AF: 0.0404

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0622

Gnomad OTH AF: 0.0626

GnomAD2 exomes AF: 0.0539 AC: 13560 AN: 251450 AF XY: 0.0577

Gnomad AFR exome AF: 0.0211

Gnomad AMR exome AF: 0.0289

Gnomad ASJ exome AF: 0.127

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.0377

Gnomad NFE exome AF: 0.0629

Gnomad OTH exome AF: 0.0609

GnomAD4 exome AF: 0.0605 AC: 88456 AN: 1461794 Hom.: 3021 Cov.: 32 AF XY: 0.0620 AC XY: 45090 AN XY: 727224

African (AFR) AF: 0.0221 AC: 740 AN: 33480

American (AMR) AF: 0.0306 AC: 1367 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 3237 AN: 26134

East Asian (EAS) AF: 0.000403 AC: 16 AN: 39700

South Asian (SAS) AF: 0.0844 AC: 7280 AN: 86250

European-Finnish (FIN) AF: 0.0434 AC: 2317 AN: 53420

Middle Eastern (MID) AF: 0.115 AC: 662 AN: 5766

European-Non Finnish (NFE) AF: 0.0621 AC: 69055 AN: 1111928

Other (OTH) AF: 0.0626 AC: 3782 AN: 60392

GnomAD4 genome AF: 0.0470 AC: 7157 AN: 152294 Hom.: 201 Cov.: 32 AF XY: 0.0452 AC XY: 3368 AN XY: 74458

African (AFR) AF: 0.0199 AC: 828 AN: 41558

American (AMR) AF: 0.0423 AC: 647 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 454 AN: 3472

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5186

South Asian (SAS) AF: 0.0791 AC: 382 AN: 4828

European-Finnish (FIN) AF: 0.0404 AC: 428 AN: 10604

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0622 AC: 4234 AN: 68022

Other (OTH) AF: 0.0614 AC: 130 AN: 2116

Alfa AF: 0.0583 Hom.: 1004

Bravo AF: 0.0454

TwinsUK AF: 0.0599 AC: 222

ALSPAC AF: 0.0612 AC: 236

ESP6500AA AF: 0.0204 AC: 90

ESP6500EA AF: 0.0649 AC: 558

ExAC AF: 0.0552 AC: 6700

Asia WGS AF: 0.0350 AC: 122 AN: 3478

EpiCase AF: 0.0655

EpiControl AF: 0.0639

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	0.97	L
PhyloP100		7.0
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.19
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.64	P
Vest4		0.57
MutPred		0.31		Loss of disorder (P = 0.1156)
MPC		0.65
ClinPred		0.026	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.54
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34774441; hg19: chr9-71851877; COSMIC: COSV55266838;