NM_001378492.1:c.-93-253T>C

Variant names:

• chr3-190387984-T-C
• rs534883127
• NM_001378492.1:c.-93-253T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_001378492.1(CLDN16):​c.-93-253T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000781 in 785,156 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (1 hom.)
• Consequence: CLDN16 NM_001378492.1 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.290
• Publications: 0 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), ClinGen, Orphanet

ENSG00000297357 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000683 (104/152230) while in subpopulation NFE AF = 0.00116 (79/68022). AF 95% confidence interval is 0.000955. There are 0 homozygotes in GnomAd4. There are 49 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.-93-253T>C		intron	N/A	NP_001365421.1	Q9Y5I7
	CLDN16	NM_001378493.1		c.-93-253T>C		intron	N/A	NP_001365422.1	Q9Y5I7
	CLDN16	NM_006580.4	MANE Select	c.-346T>C		upstream_gene	N/A	NP_006571.2	Q9Y5I7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN16	ENST00000880223.1		c.-93-253T>C		intron	N/A	ENSP00000550282.1
	CLDN16	ENST00000880225.1		c.-93-253T>C		intron	N/A	ENSP00000550284.1
	CLDN16	ENST00000880227.1		c.-93-253T>C		intron	N/A	ENSP00000550286.1

Frequencies

GnomAD3 genomes AF: 0.000684 AC: 104 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000804 AC: 509 AN: 632926 Hom.: 1 Cov.: 8 AF XY: 0.000802 AC XY: 269 AN XY: 335442

African (AFR) AF: 0.00 AC: 0 AN: 17270

American (AMR) AF: 0.000448 AC: 15 AN: 33500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18754

East Asian (EAS) AF: 0.00 AC: 0 AN: 32378

South Asian (SAS) AF: 0.000988 AC: 59 AN: 59724

European-Finnish (FIN) AF: 0.0000882 AC: 3 AN: 34032

Middle Eastern (MID) AF: 0.000351 AC: 1 AN: 2852

European-Non Finnish (NFE) AF: 0.00100 AC: 402 AN: 401416

Other (OTH) AF: 0.000879 AC: 29 AN: 33000

GnomAD4 genome AF: 0.000683 AC: 104 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.000658 AC XY: 49 AN XY: 74430

African (AFR) AF: 0.000120 AC: 5 AN: 41544

American (AMR) AF: 0.000916 AC: 14 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00116 AC: 79 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000635 Hom.: 0

Bravo AF: 0.000744

ClinVar

ClinVar submissions as Germline

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
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.9
DANN	Benign	0.40
PhyloP100		0.29
PromoterAI		-0.00070	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs534883127; hg19: chr3-190105773;