rs104893724

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_ModeratePS1_ModeratePM2PP5

The NM_006580.4(CLDN16):c.2T>C(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000684 in 1,461,854 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CLDN16
NM_006580.4 start_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 5.50

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]

CLDN16 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 30 codons. Genomic position: 190388417. Lost 0.124 part of the original CDS.

PS1

Another start lost variant in NM_006580.4 (CLDN16) was described as [Pathogenic] in Lovd

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-190388331-T-C is Pathogenic according to our data. Variant chr3-190388331-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1028522.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN16	NM_006580.4 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 5	ENST00000264734.3	NP_006571.2	Q9Y5I7
CLDN16	NM_001378492.1 link	c.2T>C	p.Met1?	start_lost	Exon 5 of 9		NP_001365421.1
CLDN16	NM_001378493.1 link	c.2T>C	p.Met1?	start_lost	Exon 4 of 8		NP_001365422.1
CLDN16	XM_047447333.1 link	c.2T>C	p.Met1?	start_lost	Exon 3 of 7		XP_047303289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CLDN16	ENST00000264734.3 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 5	1	NM_006580.4	ENSP00000264734.3	Q9Y5I7
CLDN16	ENST00000456423.2 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 2	1		ENSP00000414136.2	F6SGM4
CLDN16	ENST00000468220.1 link	n.306+13728T>C		intron_variant	Intron 3 of 4	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251028

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135666

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary hypomagnesemia

Pathogenic:1Uncertain:1

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 09, 2020

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.34

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.47

T;T

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.40

T;T

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Uncertain

0.55

MutationAssessor

Benign

0.55

N;.

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.7

D;D

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

0.65

P;D

Vest4

0.73

MutPred

0.90

Gain of catalytic residue at M71 (P = 0.0193);Gain of catalytic residue at M71 (P = 0.0193);

MVP

0.90

MPC

0.24

ClinPred

0.64

GERP RS

5.9

Varity_R

0.53

gMVP

0.73

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

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