dbSNP rs387906880: CLDN16:p.Lys205Glu (chr3-190409941-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_006580.4(CLDN16):c.613A>G(p.Lys205Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

CLDN16
NM_006580.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.44

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 Uncertain_significance. Variant got 2 ACMG points.

PM1

In a chain Claudin-16 (size 234) in uniprot entity CLD16_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_006580.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15147012).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN16	NM_006580.4 link	c.613A>G	p.Lys205Glu	missense_variant	Exon 5 of 5	ENST00000264734.3	NP_006571.2	Q9Y5I7
CLDN16	NM_001378492.1 link	c.613A>G	p.Lys205Glu	missense_variant	Exon 9 of 9		NP_001365421.1
CLDN16	NM_001378493.1 link	c.613A>G	p.Lys205Glu	missense_variant	Exon 8 of 8		NP_001365422.1
CLDN16	XM_047447333.1 link	c.613A>G	p.Lys205Glu	missense_variant	Exon 7 of 7		XP_047303289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN16	ENST00000264734.3 link	c.613A>G	p.Lys205Glu	missense_variant	Exon 5 of 5	1	NM_006580.4	ENSP00000264734.3		Q9Y5I7
CLDN16	ENST00000456423.2 link	c.*3A>G		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000414136.2		F6SGM4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251220

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135808

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:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Primary hypomagnesemia

Uncertain:1

Jan 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.034

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.24

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.61

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.65

M_CAP

Benign

0.063

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.51

MutationAssessor

Uncertain

2.5

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.3

REVEL

Benign

0.28

Sift

Benign

0.12

Sift4G

Uncertain

0.029

Polyphen

0.0

Vest4

0.14

MutPred

0.48

Loss of MoRF binding (P = 0.0096);

MVP

0.83

MPC

0.16

ClinPred

0.083

GERP RS

2.3

Varity_R

0.12

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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