NM_006580.4:c.613A>T

Variant names:

• chr3-190409941-A-T
• rs387906880
• NM_006580.4:c.613A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP3 PP5

The NM_006580.4(CLDN16):​c.613A>T​(p.Lys205*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLDN16 NM_006580.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.44
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• renal hypomagnesemia 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 3-190409941-A-T is Pathogenic according to our data. Variant chr3-190409941-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 30405.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006580.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN16	NM_006580.4	MANE Select	c.613A>T	p.Lys205*	stop_gained	Exon 5 of 5	NP_006571.2	Q9Y5I7
	CLDN16	NM_001378492.1		c.613A>T	p.Lys205*	stop_gained	Exon 9 of 9	NP_001365421.1	Q9Y5I7
	CLDN16	NM_001378493.1		c.613A>T	p.Lys205*	stop_gained	Exon 8 of 8	NP_001365422.1	Q9Y5I7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN16	ENST00000264734.3	TSL:1 MANE Select	c.613A>T	p.Lys205*	stop_gained	Exon 5 of 5	ENSP00000264734.3	Q9Y5I7
	CLDN16	ENST00000456423.2	TSL:1	c.*3A>T		3_prime_UTR	Exon 2 of 2	ENSP00000414136.2	F6SGM4
	CLDN16	ENST00000880223.1		c.613A>T	p.Lys205*	stop_gained	Exon 8 of 8	ENSP00000550282.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Primary hypomagnesemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	38
DANN	Uncertain	0.98
Eigen	Benign	0.15
Eigen_PC	Benign	-0.087
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		3.4
Vest4		0.75
GERP RS		2.3
Mutation Taster		=18/182	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.68		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.68		Position offset: -2

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

Other links and lift over

dbSNP: rs387906880; hg19: chr3-190127730;