Genetic Variant NM_199328.3:c.624T>G (chr21-30215302-A-C) – ACMG Classification: Benign (-10 pts)

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

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]

CLDN8 links:

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
CLDN8	NM_199328.3 link	c.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
CLDN8	ENST00000399899.2 link	c.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.:

Cov.:

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.:

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.:

Cov.:

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.:

Cov.:

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.:

Bravo

AF:

0.00155

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.00217

AC:

264

Asia WGS

AF:

0.000289

AC:

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

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.0081

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.61

M_CAP

Benign

0.028

MetaRNN

Benign

0.0057

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.3

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.90

REVEL

Benign

0.096

Sift

Benign

0.11

Sift4G

Benign

0.35

Polyphen

0.11

Vest4

0.16

MutPred

0.25

Gain of catalytic residue at S208 (P = 0.0286);

MVP

0.50

MPC

0.16

ClinPred

0.014

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over