rs6776378

Positions:

• chr3-190312737-G-A

Variant summary

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

The NM_021101.5(CLDN1):​c.388+135C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 931,762 control chromosomes in the GnomAD database, including 29,987 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.26 (5415 hom., cov: 33)
  • Exomes 𝑓: 0.25 (24572 hom.)
• Consequence: CLDN1 NM_021101.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.232

Genes affected

CLDN1 (HGNC:2032): (claudin 1) 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. Loss of function mutations result in neonatal ichthyosis-sclerosing cholangitis syndrome. [provided by RefSeq, Jul 2008]

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]

CLDN1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 3-190312737-G-A is Benign according to our data. Variant chr3-190312737-G-A is described in ClinVar as [Benign]. Clinvar id is 1265460.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLDN1	NM_021101.5	c.388+135C>T		intron_variant		ENST00000295522.4	NP_066924.1
CLDN16	NM_001378492.1	c.-445-2156G>A		intron_variant			NP_001365421.1
CLDN16	NM_001378493.1	c.-279+22146G>A		intron_variant			NP_001365422.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLDN1	ENST00000295522.4	c.388+135C>T		intron_variant		1	NM_021101.5	ENSP00000295522.3
CLDN1	ENST00000490800.1	n.347+135C>T		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39800 AN: 151976 Hom.: 5421 Cov.: 33

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.364

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.274

GnomAD4 exome AF: 0.249 AC: 193752 AN: 779668 Hom.: 24572 AF XY: 0.250 AC XY: 101751 AN XY: 407530

Gnomad4 AFR exome AF: 0.313

Gnomad4 AMR exome AF: 0.211

Gnomad4 ASJ exome AF: 0.249

Gnomad4 EAS exome AF: 0.174

Gnomad4 SAS exome AF: 0.270

Gnomad4 FIN exome AF: 0.183

Gnomad4 NFE exome AF: 0.256

Gnomad4 OTH exome AF: 0.253

GnomAD4 genome AF: 0.262 AC: 39818 AN: 152094 Hom.: 5415 Cov.: 33 AF XY: 0.259 AC XY: 19238 AN XY: 74340

Gnomad4 AFR AF: 0.317

Gnomad4 AMR AF: 0.230

Gnomad4 ASJ AF: 0.262

Gnomad4 EAS AF: 0.182

Gnomad4 SAS AF: 0.264

Gnomad4 FIN AF: 0.182

Gnomad4 NFE AF: 0.251

Gnomad4 OTH AF: 0.274

Alfa AF: 0.262 Hom.: 4766

Bravo AF: 0.267

Asia WGS AF: 0.232 AC: 805 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	-0.81
CADD	Benign	5.4
DANN	Benign	0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs6776378; hg19: chr3-190030526; COSMIC: COSV55045180;