NM_004817.4:c.698G>A

Variant names:

• chr9-69221242-G-A
• rs150883816
• NM_004817.4:c.698G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004817.4(TJP2):​c.698G>A​(p.Arg233Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000342 in 1,607,412 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R233R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: TJP2 NM_004817.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.89
• Publications: 1 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00434345).
• BP6: Variant 9-69221242-G-A is Benign according to our data. Variant chr9-69221242-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 165406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,Unknown,AR 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.698G>A	p.Arg233Gln	missense	Exon 5 of 23	NP_004808.2
	TJP2	NM_001170416.2		c.791G>A	p.Arg264Gln	missense	Exon 5 of 23	NP_001163887.1	Q9UDY2-7
	TJP2	NM_001369875.1		c.710G>A	p.Arg237Gln	missense	Exon 5 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.698G>A	p.Arg233Gln	missense	Exon 5 of 23	ENSP00000366453.4	Q9UDY2-1
	ENSG00000285130	ENST00000642889.1		c.1085G>A	p.Arg362Gln	missense	Exon 7 of 25	ENSP00000493780.1	A0A2R8YDH4
	TJP2	ENST00000348208.9	TSL:1	c.698G>A	p.Arg233Gln	missense	Exon 5 of 21	ENSP00000345893.4	Q9UDY2-2

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 288 AN: 152076 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00659

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000463 AC: 107 AN: 231248 AF XY: 0.000316

Gnomad AFR exome AF: 0.00681

Gnomad AMR exome AF: 0.000208

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000196

Gnomad OTH exome AF: 0.000353

GnomAD4 exome AF: 0.000180 AC: 262 AN: 1455224 Hom.: 2 Cov.: 33 AF XY: 0.000147 AC XY: 106 AN XY: 723524

African (AFR) AF: 0.00633 AC: 211 AN: 33334

American (AMR) AF: 0.000249 AC: 11 AN: 44262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25982

East Asian (EAS) AF: 0.00 AC: 0 AN: 39416

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51706

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1109426

Other (OTH) AF: 0.000400 AC: 24 AN: 60004

GnomAD4 genome AF: 0.00189 AC: 288 AN: 152188 Hom.: 0 Cov.: 33 AF XY: 0.00188 AC XY: 140 AN XY: 74404

African (AFR) AF: 0.00657 AC: 273 AN: 41554

American (AMR) AF: 0.000785 AC: 12 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00347 AC: 1 AN: 288

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67988

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000559 Hom.: 1

Bravo AF: 0.00200

ESP6500AA AF: 0.00573 AC: 25

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000573 AC: 69

Asia WGS AF: 0.000289 AC: 1 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.19	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.30	N
PhyloP100		2.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.037
Sift	Benign	0.11	T
Sift4G	Benign	0.086	T
Polyphen		0.0	B
Vest4		0.32
MVP		0.53
MPC		0.22
ClinPred		0.0028	T
GERP RS		0.53
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.023
gMVP		0.45
Mutation Taster		=100/0	polymorphism

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: rs150883816; hg19: chr9-71836158;