9-69234419-C-G

Variant names:

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

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.1672-20C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0927 in 96,294 control chromosomes in the GnomAD database, including 241 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (241 hom., cov: 23)
  • Exomes 𝑓: 0.084 (1739 hom.)
  • Failed GnomAD Quality Control
• Consequence: TJP2 NM_004817.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• 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: 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 (BayesDel_noAF=-0.76).
• BP6: Variant 9-69234419-C-G is Benign according to our data. Variant chr9-69234419-C-G is described in ClinVar as Benign. ClinVar VariationId is 259551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.103 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.1672-20C>G		intron	N/A	NP_004808.2
	TJP2	NM_001170416.2		c.1765-20C>G		intron	N/A	NP_001163887.1
	TJP2	NM_001369875.1		c.1684-20C>G		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>G		intron	N/A	ENSP00000366453.4
	ENSG00000285130	ENST00000642889.1		c.2059-20C>G		intron	N/A	ENSP00000493780.1
	TJP2	ENST00000348208.9	TSL:1	c.1672-20C>G		intron	N/A	ENSP00000345893.4

Frequencies

GnomAD3 genomes AF: 0.0927 AC: 8921 AN: 96224 Hom.: 240 Cov.: 23

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.0796

Gnomad AMR AF: 0.0747

Gnomad ASJ AF: 0.0594

Gnomad EAS AF: 0.00919

Gnomad SAS AF: 0.0975

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.0556

Gnomad NFE AF: 0.0905

Gnomad OTH AF: 0.105

GnomAD2 exomes AF: 0.0741 AC: 11239 AN: 151634 AF XY: 0.0771

Gnomad AFR exome AF: 0.0908

Gnomad AMR exome AF: 0.0484

Gnomad ASJ exome AF: 0.0613

Gnomad EAS exome AF: 0.00904

Gnomad FIN exome AF: 0.109

Gnomad NFE exome AF: 0.0746

Gnomad OTH exome AF: 0.0719

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0840 AC: 63167 AN: 752188 Hom.: 1739 Cov.: 17 AF XY: 0.0847 AC XY: 32738 AN XY: 386632

African (AFR) AF: 0.0987 AC: 1570 AN: 15908

American (AMR) AF: 0.0470 AC: 1044 AN: 22190

Ashkenazi Jewish (ASJ) AF: 0.0607 AC: 994 AN: 16380

East Asian (EAS) AF: 0.00366 AC: 106 AN: 28928

South Asian (SAS) AF: 0.101 AC: 4519 AN: 44964

European-Finnish (FIN) AF: 0.107 AC: 4344 AN: 40548

Middle Eastern (MID) AF: 0.0804 AC: 266 AN: 3308

European-Non Finnish (NFE) AF: 0.0871 AC: 47605 AN: 546388

Other (OTH) AF: 0.0810 AC: 2719 AN: 33574

GnomAD4 genome AF: 0.0927 AC: 8926 AN: 96294 Hom.: 241 Cov.: 23 AF XY: 0.0936 AC XY: 4375 AN XY: 46750

African (AFR) AF: 0.106 AC: 2644 AN: 24972

American (AMR) AF: 0.0745 AC: 684 AN: 9186

Ashkenazi Jewish (ASJ) AF: 0.0594 AC: 136 AN: 2288

East Asian (EAS) AF: 0.00890 AC: 29 AN: 3260

South Asian (SAS) AF: 0.0982 AC: 301 AN: 3064

European-Finnish (FIN) AF: 0.135 AC: 862 AN: 6404

Middle Eastern (MID) AF: 0.0611 AC: 11 AN: 180

European-Non Finnish (NFE) AF: 0.0905 AC: 4078 AN: 45056

Other (OTH) AF: 0.103 AC: 135 AN: 1306

Alfa AF: 0.00955 Hom.: 1

Bravo AF: 0.0590

ClinVar

ClinVar submissions as Germline

Significance: 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
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.3
DANN	Benign	0.67
PhyloP100		-0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs80014470; hg19: chr9-71849335;