3-190326718-T-C

Variant names:

• chr3-190326718-T-C
• rs3954259
• NM_001378492.1:c.-279+11659T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001378492.1(CLDN16):​c.-279+11659T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.563 in 151,960 control chromosomes in the GnomAD database, including 25,081 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.56 (25081 hom., cov: 31)
• Consequence: CLDN16 NM_001378492.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.494
• Publications: 2 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.728 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378492.1. 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_001378492.1		c.-279+11659T>C		intron	N/A	NP_001365421.1	Q9Y5I7
	CLDN16	NM_001378493.1		c.-279+36127T>C		intron	N/A	NP_001365422.1	Q9Y5I7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN16	ENST00000880223.1		c.-279+4057T>C		intron	N/A	ENSP00000550282.1
	CLDN16	ENST00000880225.1		c.-302+4057T>C		intron	N/A	ENSP00000550284.1
	CLDN16	ENST00000880227.1		c.-94+4057T>C		intron	N/A	ENSP00000550286.1

Frequencies

GnomAD3 genomes AF: 0.563 AC: 85432 AN: 151840 Hom.: 25070 Cov.: 31

Gnomad AFR AF: 0.736

Gnomad AMI AF: 0.623

Gnomad AMR AF: 0.525

Gnomad ASJ AF: 0.466

Gnomad EAS AF: 0.703

Gnomad SAS AF: 0.466

Gnomad FIN AF: 0.487

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.479

Gnomad OTH AF: 0.528

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.563 AC: 85492 AN: 151960 Hom.: 25081 Cov.: 31 AF XY: 0.560 AC XY: 41566 AN XY: 74240

African (AFR) AF: 0.735 AC: 30485 AN: 41460

American (AMR) AF: 0.526 AC: 8030 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.466 AC: 1614 AN: 3466

East Asian (EAS) AF: 0.702 AC: 3619 AN: 5152

South Asian (SAS) AF: 0.466 AC: 2238 AN: 4806

European-Finnish (FIN) AF: 0.487 AC: 5143 AN: 10550

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.479 AC: 32508 AN: 67934

Other (OTH) AF: 0.528 AC: 1116 AN: 2112

Alfa AF: 0.530 Hom.: 2732

Bravo AF: 0.579

Asia WGS AF: 0.607 AC: 2109 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.9
DANN	Benign	0.62
PhyloP100		0.49

Splicing

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

Other links and lift over

dbSNP: rs3954259; hg19: chr3-190044507;