3-190321812-G-C

Position:

• chr3-190321812-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021101.5(CLDN1):​c.223+172C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.463 in 151,990 control chromosomes in the GnomAD database, including 16,627 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.46 (16627 hom., cov: 32)
• Consequence: CLDN1 NM_021101.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.11

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 3-190321812-G-C is Benign according to our data. Variant chr3-190321812-G-C is described in ClinVar as [Benign]. Clinvar id is 1246415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.747 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLDN1	NM_021101.5	c.223+172C>G		intron_variant		ENST00000295522.4	NP_066924.1
CLDN16	NM_001378492.1	c.-279+6753G>C		intron_variant			NP_001365421.1
CLDN16	NM_001378493.1	c.-279+31221G>C		intron_variant			NP_001365422.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLDN1	ENST00000295522.4	c.223+172C>G		intron_variant		1	NM_021101.5	ENSP00000295522.3

Frequencies

GnomAD3 genomes AF: 0.463 AC: 70366 AN: 151872 Hom.: 16624 Cov.: 32

Gnomad AFR AF: 0.500

Gnomad AMI AF: 0.607

Gnomad AMR AF: 0.472

Gnomad ASJ AF: 0.493

Gnomad EAS AF: 0.767

Gnomad SAS AF: 0.405

Gnomad FIN AF: 0.426

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.422

Gnomad OTH AF: 0.447

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

GnomAD4 genome AF: 0.463 AC: 70391 AN: 151990 Hom.: 16627 Cov.: 32 AF XY: 0.465 AC XY: 34528 AN XY: 74290

Gnomad4 AFR AF: 0.500

Gnomad4 AMR AF: 0.472

Gnomad4 ASJ AF: 0.493

Gnomad4 EAS AF: 0.767

Gnomad4 SAS AF: 0.404

Gnomad4 FIN AF: 0.426

Gnomad4 NFE AF: 0.422

Gnomad4 OTH AF: 0.445

Alfa AF: 0.311 Hom.: 831

Bravo AF: 0.472

Asia WGS AF: 0.556 AC: 1932 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.1
DANN	Benign	0.56

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: rs893051; hg19: chr3-190039601;