NM_004817.4:c.1877C>G

Variant names:

• chr9-69236124-C-G
• rs149911553
• NM_004817.4:c.1877C>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_004817.4(TJP2):​c.1877C>G​(p.Thr626Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,614,170 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T626T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: TJP2 NM_004817.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.654
• Publications: 10 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02687785).
• BP6: Variant 9-69236124-C-G is Benign according to our data. Variant chr9-69236124-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44093.
• 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.1877C>G	p.Thr626Ser	missense	Exon 13 of 23	NP_004808.2
	TJP2	NM_001170416.2		c.1970C>G	p.Thr657Ser	missense	Exon 13 of 23	NP_001163887.1	Q9UDY2-7
	TJP2	NM_001369875.1		c.1889C>G	p.Thr630Ser	missense	Exon 13 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.1877C>G	p.Thr626Ser	missense	Exon 13 of 23	ENSP00000366453.4	Q9UDY2-1
	ENSG00000285130	ENST00000642889.1		c.2264C>G	p.Thr755Ser	missense	Exon 15 of 25	ENSP00000493780.1	A0A2R8YDH4
	TJP2	ENST00000348208.9	TSL:1	c.1877C>G	p.Thr626Ser	missense	Exon 13 of 21	ENSP00000345893.4	Q9UDY2-2

Frequencies

GnomAD3 genomes AF: 0.00104 AC: 158 AN: 152160 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00203

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00101 AC: 253 AN: 251442 AF XY: 0.000920

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.00178

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.00138 AC: 2023 AN: 1461892 Hom.: 2 Cov.: 32 AF XY: 0.00135 AC XY: 982 AN XY: 727246

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.000715 AC: 32 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000689 AC: 18 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86256

European-Finnish (FIN) AF: 0.000318 AC: 17 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00169 AC: 1877 AN: 1112012

Other (OTH) AF: 0.000729 AC: 44 AN: 60396

GnomAD4 genome AF: 0.00104 AC: 158 AN: 152278 Hom.: 1 Cov.: 32 AF XY: 0.000900 AC XY: 67 AN XY: 74450

African (AFR) AF: 0.000168 AC: 7 AN: 41558

American (AMR) AF: 0.000196 AC: 3 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00203 AC: 138 AN: 68012

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00150 Hom.: 1

Bravo AF: 0.000831

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000939 AC: 114

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.00190

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	not specified (2)
-	-	1	TJP2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.089	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.090	N
PhyloP100		0.65
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.016
Sift	Benign	0.27	T
Sift4G	Benign	0.17	T
Polyphen		0.0020	B
Vest4		0.17
MutPred		0.33		Loss of sheet (P = 0.0457)
MVP		0.39
MPC		0.18
ClinPred		0.018	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.048
gMVP		0.20
Mutation Taster		=99/1	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: rs149911553; hg19: chr9-71851040; COSMIC: COSV105036786;