rs56235513

chr3-190322667-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The XM_047447333.1(CLDN16):c.-170+6G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 231,914 control chromosomes in the GnomAD database, including 1,558 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.10 (988 hom., cov: 32)
  • Exomes 𝑓: 0.11 (570 hom.)
• Consequence: CLDN16 XM_047447333.1 splice_donor_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.56

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 3-190322667-G-A is Benign according to our data. Variant chr3-190322667-G-A is described in ClinVar as [Benign]. Clinvar id is 1267401.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLDN16	NM_001378492.1	c.-279+7608G>A		intron_variant
CLDN16	NM_001378493.1	c.-279+32076G>A		intron_variant
CLDN16	XM_047447333.1	c.-170+6G>A		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLDN16	ENST00000468220.1	n.121+6G>A		splice_donor_region_variant, intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15798 AN: 152150 Hom.: 985 Cov.: 32

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.224

Gnomad SAS AF: 0.177

Gnomad FIN AF: 0.0628

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0774

Gnomad OTH AF: 0.124

GnomAD4 exome AF: 0.107 AC: 8557 AN: 79646 Hom.: 570 Cov.: 0 AF XY: 0.117 AC XY: 4836 AN XY: 41352

Gnomad4 AFR exome AF: 0.105

Gnomad4 AMR exome AF: 0.179

Gnomad4 ASJ exome AF: 0.106

Gnomad4 EAS exome AF: 0.215

Gnomad4 SAS exome AF: 0.181

Gnomad4 FIN exome AF: 0.0705

Gnomad4 NFE exome AF: 0.0839

Gnomad4 OTH exome AF: 0.0897

GnomAD4 genome AF: 0.104 AC: 15832 AN: 152268 Hom.: 988 Cov.: 32 AF XY: 0.107 AC XY: 7997 AN XY: 74454

Gnomad4 AFR AF: 0.114

Gnomad4 AMR AF: 0.162

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.224

Gnomad4 SAS AF: 0.177

Gnomad4 FIN AF: 0.0628

Gnomad4 NFE AF: 0.0775

Gnomad4 OTH AF: 0.126

Alfa AF: 0.0848 Hom.: 81

Bravo AF: 0.111

Asia WGS AF: 0.198 AC: 687 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.98
Dann	Benign	0.83

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs56235513; hg19: chr3-190040456;