X-9967544-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001195081.2(CLDN34):​c.187C>T​(p.Arg63Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000096 in 1,042,183 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R63G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 22)
Exomes 𝑓: 9.6e-7 ( 0 hom. 1 hem. )

Consequence

CLDN34
NM_001195081.2 missense

Scores

2
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.92
Variant links:
Genes affected
CLDN34 (HGNC:51259): (claudin 34) Predicted to enable structural molecule activity. Predicted to be involved in bicellular tight junction assembly and cell adhesion. Predicted to be integral component of membrane. Predicted to be active in bicellular tight junction and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.11695701).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CLDN34NM_001195081.2 linkc.187C>T p.Arg63Cys missense_variant Exon 1 of 1 ENST00000445307.4 NP_001182010.1 H7C241

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CLDN34ENST00000445307.4 linkc.187C>T p.Arg63Cys missense_variant Exon 1 of 1 6 NM_001195081.2 ENSP00000403980.3 H7C241

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
AF:
9.60e-7
AC:
1
AN:
1042183
Hom.:
0
Cov.:
34
AF XY:
0.00000293
AC XY:
1
AN XY:
341115
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000122
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
22

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 09, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.187C>T (p.R63C) alteration is located in exon 1 (coding exon 1) of the CLDN34 gene. This alteration results from a C to T substitution at nucleotide position 187, causing the arginine (R) at amino acid position 63 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.48
T
BayesDel_noAF
Benign
-0.93
CADD
Benign
0.19
DANN
Benign
0.96
DEOGEN2
Benign
0.014
T
FATHMM_MKL
Benign
0.0074
N
LIST_S2
Benign
0.41
T
MetaRNN
Benign
0.12
T
MetaSVM
Benign
-1.0
T
PrimateAI
Benign
0.19
T
PROVEAN
Uncertain
-2.5
N
REVEL
Benign
0.012
Sift
Uncertain
0.0040
D
Sift4G
Benign
0.15
T
Vest4
0.16
MVP
0.17
ClinPred
0.083
T
GERP RS
-7.6
Varity_R
0.079
gMVP
0.52

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-9935584; API