3-190310483-A-T

Variant names:

• chr3-190310483-A-T
• rs3774028
• NM_021101.5:c.389-230T>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_021101.5(CLDN1):​c.389-230T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 152,108 control chromosomes in the GnomAD database, including 5,755 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.25 (5755 hom., cov: 32)
• Consequence: CLDN1 NM_021101.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.125
• Publications: 2 publications found

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]

P3H2-AS1 (HGNC:40886): (P3H2 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 3-190310483-A-T is Benign according to our data. Variant chr3-190310483-A-T is described in ClinVar as [Benign]. Clinvar id is 1277417.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.34 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN1	NM_021101.5	c.389-230T>A		intron_variant	Intron 2 of 3	ENST00000295522.4	NP_066924.1
CLDN16	NM_001378492.1	c.-445-4410A>T		intron_variant	Intron 1 of 8		NP_001365421.1
CLDN16	NM_001378493.1	c.-279+19892A>T		intron_variant	Intron 1 of 7		NP_001365422.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN1	ENST00000295522.4	c.389-230T>A		intron_variant	Intron 2 of 3	1	NM_021101.5	ENSP00000295522.3
CLDN1	ENST00000490800.1	n.348-230T>A		intron_variant	Intron 1 of 1	2
P3H2-AS1	ENST00000747181.1	n.627-4410A>T		intron_variant	Intron 5 of 6

Frequencies

GnomAD3 genomes AF: 0.250 AC: 38005 AN: 151990 Hom.: 5754 Cov.: 32

Gnomad AFR AF: 0.0846

Gnomad AMI AF: 0.253

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.411

Gnomad EAS AF: 0.0875

Gnomad SAS AF: 0.355

Gnomad FIN AF: 0.322

Gnomad MID AF: 0.363

Gnomad NFE AF: 0.325

Gnomad OTH AF: 0.266

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

GnomAD4 genome AF: 0.250 AC: 38005 AN: 152108 Hom.: 5755 Cov.: 32 AF XY: 0.251 AC XY: 18683 AN XY: 74346

African (AFR) AF: 0.0844 AC: 3505 AN: 41536

American (AMR) AF: 0.295 AC: 4509 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.411 AC: 1426 AN: 3468

East Asian (EAS) AF: 0.0877 AC: 454 AN: 5178

South Asian (SAS) AF: 0.354 AC: 1710 AN: 4824

European-Finnish (FIN) AF: 0.322 AC: 3389 AN: 10536

Middle Eastern (MID) AF: 0.356 AC: 104 AN: 292

European-Non Finnish (NFE) AF: 0.325 AC: 22120 AN: 67966

Other (OTH) AF: 0.263 AC: 557 AN: 2114

Alfa AF: 0.150 Hom.: 317

Bravo AF: 0.237

Asia WGS AF: 0.244 AC: 852 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.98
DANN	Benign	0.42
PhyloP100		-0.13
Mutation Taster		=100/0	polymorphism (auto)

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: rs3774028; hg19: chr3-190028272;