3-190402428-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The NM_006580.4(CLDN16):​c.206C>T​(p.Ala69Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000868 in 1,612,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A69A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

CLDN16
NM_006580.4 missense

Scores

7
10
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 5.65
Variant links:
Genes affected
CLDN16 (HGNC:2037): (claudin 16) Tight junctions represent one mode of cell-to-cell adhesion in epithelial or endothelial cell sheets, forming continuous seals around cells and serving as a physical barrier to prevent solutes and water from passing freely through the paracellular space. These junctions are comprised of sets of continuous networking strands in the outwardly facing cytoplasmic leaflet, with complementary grooves in the inwardly facing extracytoplasmic leaflet. The protein encoded by this gene, a member of the claudin family, is an integral membrane protein and a component of tight junction strands. It is found primarily in the kidneys, specifically in the thick ascending limb of Henle, where it acts as either an intercellular pore or ion concentration sensor to regulate the paracellular resorption of magnesium ions. Defects in this gene are a cause of primary hypomagnesemia, which is characterized by massive renal magnesium wasting with hypomagnesemia and hypercalciuria, resulting in nephrocalcinosis and renal failure. This gene and the CLDN1 gene are clustered on chromosome 3q28. [provided by RefSeq, Jun 2010]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a topological_domain Extracellular (size 54) in uniprot entity CLD16_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_006580.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
Variant 3-190402428-C-T is Pathogenic according to our data. Variant chr3-190402428-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 545702.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CLDN16NM_006580.4 linkc.206C>T p.Ala69Val missense_variant Exon 2 of 5 ENST00000264734.3 NP_006571.2 Q9Y5I7
CLDN16NM_001378492.1 linkc.206C>T p.Ala69Val missense_variant Exon 6 of 9 NP_001365421.1
CLDN16NM_001378493.1 linkc.206C>T p.Ala69Val missense_variant Exon 5 of 8 NP_001365422.1
CLDN16XM_047447333.1 linkc.206C>T p.Ala69Val missense_variant Exon 4 of 7 XP_047303289.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CLDN16ENST00000264734.3 linkc.206C>T p.Ala69Val missense_variant Exon 2 of 5 1 NM_006580.4 ENSP00000264734.3 Q9Y5I7
CLDN16ENST00000456423.2 linkc.115-7475C>T intron_variant Intron 1 of 1 1 ENSP00000414136.2 F6SGM4
CLDN16ENST00000468220.1 linkn.398C>T non_coding_transcript_exon_variant Exon 4 of 5 4

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
151952
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000208
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251426
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135876
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000822
AC:
12
AN:
1460320
Hom.:
0
Cov.:
30
AF XY:
0.0000110
AC XY:
8
AN XY:
726610
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
151952
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74190
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Primary hypomagnesemia Pathogenic:2
Mar 05, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 29, 2018
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.53
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.33
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.89
D
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.91
D
M_CAP
Pathogenic
0.31
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Uncertain
0.74
D
MutationAssessor
Uncertain
2.6
M
PrimateAI
Uncertain
0.66
T
PROVEAN
Uncertain
-2.6
D
REVEL
Pathogenic
0.72
Sift
Benign
0.035
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.94
MutPred
0.90
Loss of ubiquitination at K144 (P = 0.2243);
MVP
0.95
MPC
0.37
ClinPred
0.96
D
GERP RS
5.7
Varity_R
0.57
gMVP
0.58

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
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: rs765256758; hg19: chr3-190120217; COSMIC: COSV99290296; API