rs12340440

Variant names:

• chr9-69236164-C-A
• rs12340440
• NM_004817.4:c.1917C>A

Your query was ambiguous. Multiple possible variants found:

• chr9-69236164-C-A
• chr9-69236164-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004817.4(TJP2):​c.1917C>A​(p.Asp639Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D639D) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TJP2 NM_004817.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.175
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TJP2	NM_004817.4	c.1917C>A	p.Asp639Glu	missense_variant	Exon 13 of 23	ENST00000377245.9	NP_004808.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TJP2	ENST00000377245.9	c.1917C>A	p.Asp639Glu	missense_variant	Exon 13 of 23	1	NM_004817.4	ENSP00000366453.4
ENSG00000285130	ENST00000642889.1	c.2304C>A	p.Asp768Glu	missense_variant	Exon 15 of 25			ENSP00000493780.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	.;.;.;.;T;.;T;.;.;.;.;.;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.91	D;D;D;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.47	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	.;.;.;.;L;L;L;.;.;.;.;.;.;.
PhyloP100		0.17
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.3	.;N;.;.;.;N;N;.;.;.;N;.;N;.
REVEL	Benign	0.23
Sift	Benign	0.051	.;T;.;.;.;D;D;.;.;.;D;.;D;.
Sift4G	Benign	0.11	.;T;.;.;.;T;T;.;.;.;T;.;T;.
Polyphen		1.0, 1.0	.;.;.;.;D;D;D;.;.;.;.;.;.;.
Vest4		0.57, 0.57, 0.56, 0.57, 0.53
MutPred		0.45		.;.;.;.;Loss of ubiquitination at K641 (P = 0.0982);Loss of ubiquitination at K641 (P = 0.0982);Loss of ubiquitination at K641 (P = 0.0982);Loss of ubiquitination at K641 (P = 0.0982);Loss of ubiquitination at K641 (P = 0.0982);.;.;.;.;.;
MVP		0.63
MPC		0.71
ClinPred		0.94	D
GERP RS		-3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.12
gMVP		0.36
Mutation Taster		=80/20	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

Other links and lift over

dbSNP: rs12340440; hg19: chr9-71851080;