9-69234419-C-T

Variant names:

• chr9-69234419-C-T
• rs80014470
• NM_004817.4:c.1672-20C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004817.4(TJP2):​c.1672-20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.022 (0 hom., cov: 23)
  • Exomes 𝑓: 0.041 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TJP2 NM_004817.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.589
• Publications: 2 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, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics
• 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, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia

ENSG00000285130 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).

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.1672-20C>T		intron	N/A	NP_004808.2
	TJP2	NM_001170416.2		c.1765-20C>T		intron	N/A	NP_001163887.1	Q9UDY2-7
	TJP2	NM_001369875.1		c.1684-20C>T		intron	N/A	NP_001356804.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TJP2	ENST00000377245.9	TSL:1 MANE Select	c.1672-20C>T		intron	N/A	ENSP00000366453.4	Q9UDY2-1
	ENSG00000285130	ENST00000642889.1		c.2059-20C>T		intron	N/A	ENSP00000493780.1	A0A2R8YDH4
	TJP2	ENST00000348208.9	TSL:1	c.1672-20C>T		intron	N/A	ENSP00000345893.4	Q9UDY2-2

Frequencies

GnomAD3 genomes AF: 0.0225 AC: 1945 AN: 86400 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0237

Gnomad AMI AF: 0.0314

Gnomad AMR AF: 0.0170

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.0106

Gnomad SAS AF: 0.0164

Gnomad FIN AF: 0.0150

Gnomad MID AF: 0.00532

Gnomad NFE AF: 0.0256

Gnomad OTH AF: 0.0170

GnomAD2 exomes AF: 0.0602 AC: 9124 AN: 151634 AF XY: 0.0556

Gnomad AFR exome AF: 0.0585

Gnomad AMR exome AF: 0.116

Gnomad ASJ exome AF: 0.0461

Gnomad EAS exome AF: 0.143

Gnomad FIN exome AF: 0.0333

Gnomad NFE exome AF: 0.0445

Gnomad OTH exome AF: 0.0912

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0405 AC: 29813 AN: 735530 Hom.: 0 Cov.: 17 AF XY: 0.0428 AC XY: 16162 AN XY: 377330

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0426 AC: 664 AN: 15590

American (AMR) AF: 0.0892 AC: 1871 AN: 20966

Ashkenazi Jewish (ASJ) AF: 0.0470 AC: 745 AN: 15864

East Asian (EAS) AF: 0.0497 AC: 1413 AN: 28442

South Asian (SAS) AF: 0.145 AC: 6050 AN: 41582

European-Finnish (FIN) AF: 0.0473 AC: 1837 AN: 38820

Middle Eastern (MID) AF: 0.0300 AC: 97 AN: 3232

European-Non Finnish (NFE) AF: 0.0293 AC: 15767 AN: 538210

Other (OTH) AF: 0.0417 AC: 1369 AN: 32824

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0225 AC: 1945 AN: 86466 Hom.: 0 Cov.: 23 AF XY: 0.0207 AC XY: 880 AN XY: 42528

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0236 AC: 533 AN: 22550

American (AMR) AF: 0.0168 AC: 145 AN: 8618

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 48 AN: 1962

East Asian (EAS) AF: 0.0106 AC: 32 AN: 3006

South Asian (SAS) AF: 0.0165 AC: 48 AN: 2912

European-Finnish (FIN) AF: 0.0150 AC: 93 AN: 6206

Middle Eastern (MID) AF: 0.00581 AC: 1 AN: 172

European-Non Finnish (NFE) AF: 0.0256 AC: 1008 AN: 39336

Other (OTH) AF: 0.0176 AC: 21 AN: 1194

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0244 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.2
DANN	Benign	0.67
PhyloP100		-0.59
Mutation Taster		=100/0	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs80014470;

hg19: chr9-71849335;