rs387906880

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr3-190409941-A-G
• chr3-190409941-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_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. 16/22 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U: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: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a chain Claudin-16 (size 234) in uniprot entity CLD16_HUMAN there are 30 pathogenic changes around while only 4 benign (88%) in NM_006580.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 22 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: -0.076836 (below the threshold of 3.09). Trascript score misZ: 0.28069 (below the threshold of 3.09). GenCC associations: The gene is linked to renal hypomagnesemia 3.
• BP4: Computational evidence support a benign effect (MetaRNN=0.15147012).

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>G	p.Lys205Glu	missense	Exon 5 of 5	NP_006571.2	Q9Y5I7
	CLDN16	NM_001378492.1		c.613A>G	p.Lys205Glu	missense	Exon 9 of 9	NP_001365421.1	Q9Y5I7
	CLDN16	NM_001378493.1		c.613A>G	p.Lys205Glu	missense	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>G	p.Lys205Glu	missense	Exon 5 of 5	ENSP00000264734.3	Q9Y5I7
	CLDN16	ENST00000456423.2	TSL:1	c.*3A>G		3_prime_UTR	Exon 2 of 2	ENSP00000414136.2	F6SGM4
	CLDN16	ENST00000880223.1		c.613A>G	p.Lys205Glu	missense	Exon 8 of 8	ENSP00000550282.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251220 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Benign	0.89
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.4
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.28
Sift	Benign	0.12	T
Sift4G	Uncertain	0.029	D
Polyphen		0.0	B
Vest4		0.14
MutPred		0.48		Loss of MoRF binding (P = 0.0096)
MVP		0.83
MPC		0.16
ClinPred		0.083	T
GERP RS		2.3
Varity_R		0.12
gMVP		0.43
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs387906880; hg19: chr3-190127730;