3-190352446-T-C

Variant names:

• chr3-190352446-T-C
• rs1425101
• NM_001378492.1:c.-278-18447T>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.-278-18447T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.925 in 152,132 control chromosomes in the GnomAD database, including 65,112 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 0.93 (65112 hom., cov: 32)
• Consequence: CLDN16 NM_001378492.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0720
• 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=-0.56).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 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.-278-18447T>C		intron	N/A	NP_001365421.1	Q9Y5I7
	CLDN16	NM_001378493.1		c.-278-18447T>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.-278-18447T>C		intron	N/A	ENSP00000550282.1
	CLDN16	ENST00000880225.1		c.-301-18424T>C		intron	N/A	ENSP00000550284.1
	CLDN16	ENST00000880227.1		c.-94+29785T>C		intron	N/A	ENSP00000550286.1

Frequencies

GnomAD3 genomes AF: 0.925 AC: 140670 AN: 152014 Hom.: 65087 Cov.: 32

Gnomad AFR AF: 0.920

Gnomad AMI AF: 0.955

Gnomad AMR AF: 0.924

Gnomad ASJ AF: 0.913

Gnomad EAS AF: 0.996

Gnomad SAS AF: 0.867

Gnomad FIN AF: 0.914

Gnomad MID AF: 0.975

Gnomad NFE AF: 0.929

Gnomad OTH AF: 0.931

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

GnomAD4 genome AF: 0.925 AC: 140751 AN: 152132 Hom.: 65112 Cov.: 32 AF XY: 0.924 AC XY: 68676 AN XY: 74364

African (AFR) AF: 0.920 AC: 38198 AN: 41536

American (AMR) AF: 0.924 AC: 14103 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.913 AC: 3171 AN: 3472

East Asian (EAS) AF: 0.996 AC: 5133 AN: 5152

South Asian (SAS) AF: 0.867 AC: 4182 AN: 4824

European-Finnish (FIN) AF: 0.914 AC: 9684 AN: 10592

Middle Eastern (MID) AF: 0.976 AC: 287 AN: 294

European-Non Finnish (NFE) AF: 0.929 AC: 63167 AN: 67974

Other (OTH) AF: 0.925 AC: 1955 AN: 2114

Alfa AF: 0.931 Hom.: 8180

Bravo AF: 0.929

Asia WGS AF: 0.926 AC: 3221 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	11
DANN	Benign	0.87
PhyloP100		0.072

Splicing

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

Other links and lift over

dbSNP: rs1425101; hg19: chr3-190070235;