chr3-190311158-T-C

Variant names:

• chr3-190311158-T-C
• rs3774025
• NM_021101.5:c.389-905A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021101.5(CLDN1):​c.389-905A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.661 in 151,946 control chromosomes in the GnomAD database, including 34,157 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.66 (34157 hom., cov: 31)
• Consequence: CLDN1 NM_021101.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.42
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.812 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021101.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN1	NM_021101.5	MANE Select	c.389-905A>G		intron	N/A	NP_066924.1
	CLDN16	NM_001378492.1		c.-445-3735T>C		intron	N/A	NP_001365421.1
	CLDN16	NM_001378493.1		c.-279+20567T>C		intron	N/A	NP_001365422.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN1	ENST00000295522.4	TSL:1 MANE Select	c.389-905A>G		intron	N/A	ENSP00000295522.3
	CLDN1	ENST00000490800.1	TSL:2	n.348-905A>G		intron	N/A
	P3H2-AS1	ENST00000747181.1		n.627-3735T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.661 AC: 100344 AN: 151828 Hom.: 34114 Cov.: 31

Gnomad AFR AF: 0.820

Gnomad AMI AF: 0.748

Gnomad AMR AF: 0.615

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.808

Gnomad SAS AF: 0.550

Gnomad FIN AF: 0.579

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.591

Gnomad OTH AF: 0.648

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

GnomAD4 genome AF: 0.661 AC: 100433 AN: 151946 Hom.: 34157 Cov.: 31 AF XY: 0.659 AC XY: 48929 AN XY: 74258

African (AFR) AF: 0.820 AC: 33986 AN: 41458

American (AMR) AF: 0.614 AC: 9385 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.510 AC: 1767 AN: 3466

East Asian (EAS) AF: 0.807 AC: 4157 AN: 5148

South Asian (SAS) AF: 0.550 AC: 2644 AN: 4804

European-Finnish (FIN) AF: 0.579 AC: 6100 AN: 10532

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.591 AC: 40177 AN: 67948

Other (OTH) AF: 0.645 AC: 1360 AN: 2110

Alfa AF: 0.600 Hom.: 3606

Bravo AF: 0.673

Asia WGS AF: 0.622 AC: 2162 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.28
DANN	Benign	0.58
PhyloP100		-2.4
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: rs3774025; hg19: chr3-190028947; COSMIC: COSV55044784;