21-30215463-C-A

Variant names:

• chr21-30215463-C-A
• NM_199328.3:c.463G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_199328.3(CLDN8):​c.463G>T​(p.Val155Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLDN8 NM_199328.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.13
• Publications: 0 publications found

Genes affected

CLDN8 (HGNC:2050): (claudin 8) This gene encodes a member of the claudin family. Claudins are integral membrane proteins and components of tight junction strands. Tight junction strands serve as a physical barrier to prevent solutes and water from passing freely through the paracellular space between epithelial or endothelial cell sheets, and also play critical roles in maintaining cell polarity and signal transductions. This protein plays important roles in the paracellular cation barrier of the distal renal tubule, and in the paracellular barrier to prevent sodium back-leakage in distal colon. Differential expression of this gene has been observed in colorectal carcinoma and renal cell tumors, and along with claudin-7, is an immunohistochemical marker for the differential diagnosis of chromophobe renal cell carcinoma and renal oncocytoma.[provided by RefSeq, May 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19203901).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199328.3. 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
	CLDN8	NM_199328.3	MANE Select	c.463G>T	p.Val155Phe	missense	Exon 1 of 1	NP_955360.1	P56748

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN8	ENST00000399899.2	TSL:6 MANE Select	c.463G>T	p.Val155Phe	missense	Exon 1 of 1	ENSP00000382783.1	P56748

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	7.0
DANN	Benign	0.96
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.16	T
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.9	L
PhyloP100		-1.1
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.35
Sift	Benign	0.048	D
Sift4G	Uncertain	0.035	D
Polyphen		0.62	P
Vest4		0.22
MutPred		0.35		Gain of helix (P = 0.1736)
MVP		0.59
MPC		0.17
ClinPred		0.29	T
GERP RS		-5.1
Varity_R		0.076
gMVP		0.49
Mutation Taster		=97/3	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

hg19: chr21-31587781;