NM_199328.3:c.624T>G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_199328.3(CLDN8):​c.624T>G​(p.Ser208Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 1,614,150 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S208I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0024 ( 5 hom. )

Consequence

CLDN8
NM_199328.3 missense

Scores

1
18

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.778
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0057043135).
BP6
Variant 21-30215302-A-C is Benign according to our data. Variant chr21-30215302-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 3390330.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CLDN8NM_199328.3 linkc.624T>G p.Ser208Arg missense_variant Exon 1 of 1 ENST00000399899.2 NP_955360.1 P56748A0A0K0K1I9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CLDN8ENST00000399899.2 linkc.624T>G p.Ser208Arg missense_variant Exon 1 of 1 6 NM_199328.3 ENSP00000382783.1 P56748

Frequencies

GnomAD3 genomes
AF:
0.00191
AC:
290
AN:
152162
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000579
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000589
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00151
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00348
Gnomad OTH
AF:
0.00191
GnomAD3 exomes
AF:
0.00210
AC:
528
AN:
251442
Hom.:
1
AF XY:
0.00213
AC XY:
290
AN XY:
135886
show subpopulations
Gnomad AFR exome
AF:
0.000800
Gnomad AMR exome
AF:
0.000549
Gnomad ASJ exome
AF:
0.0000992
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00208
Gnomad NFE exome
AF:
0.00386
Gnomad OTH exome
AF:
0.00179
GnomAD4 exome
AF:
0.00238
AC:
3482
AN:
1461870
Hom.:
5
Cov.:
31
AF XY:
0.00232
AC XY:
1690
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.000687
Gnomad4 AMR exome
AF:
0.000559
Gnomad4 ASJ exome
AF:
0.0000765
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00286
Gnomad4 NFE exome
AF:
0.00286
Gnomad4 OTH exome
AF:
0.00161
GnomAD4 genome
AF:
0.00190
AC:
290
AN:
152280
Hom.:
1
Cov.:
32
AF XY:
0.00168
AC XY:
125
AN XY:
74450
show subpopulations
Gnomad4 AFR
AF:
0.000577
Gnomad4 AMR
AF:
0.000588
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00151
Gnomad4 NFE
AF:
0.00348
Gnomad4 OTH
AF:
0.00189
Alfa
AF:
0.00214
Hom.:
4
Bravo
AF:
0.00155
TwinsUK
AF:
0.00216
AC:
8
ALSPAC
AF:
0.00234
AC:
9
ESP6500AA
AF:
0.00182
AC:
8
ESP6500EA
AF:
0.00221
AC:
19
ExAC
AF:
0.00217
AC:
264
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00267
EpiControl
AF:
0.00296

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Sep 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

CLDN8: BP4 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Benign
-0.42
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
15
DANN
Benign
0.92
DEOGEN2
Benign
0.0081
T
Eigen
Benign
-0.98
Eigen_PC
Benign
-0.96
FATHMM_MKL
Benign
0.16
N
LIST_S2
Benign
0.61
T
M_CAP
Benign
0.028
D
MetaRNN
Benign
0.0057
T
MetaSVM
Benign
-0.85
T
MutationAssessor
Uncertain
2.3
M
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-0.90
N
REVEL
Benign
0.096
Sift
Benign
0.11
T
Sift4G
Benign
0.35
T
Polyphen
0.11
B
Vest4
0.16
MutPred
0.25
Gain of catalytic residue at S208 (P = 0.0286);
MVP
0.50
MPC
0.16
ClinPred
0.014
T
GERP RS
-0.26
Varity_R
0.072
gMVP
0.51

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs146073584; hg19: chr21-31587620; API