rs11717803

Variant names:

• chr3-190317579-A-G
• rs11717803
• NM_021101.5:c.223+4405T>C

Variant summary

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

The NM_021101.5(CLDN1):​c.223+4405T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0456 in 152,302 control chromosomes in the GnomAD database, including 269 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 0.046 (269 hom., cov: 32)
• Consequence: CLDN1 NM_021101.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.127
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0954 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN1	NM_021101.5	c.223+4405T>C		intron_variant	Intron 1 of 3	ENST00000295522.4	NP_066924.1
CLDN16	NM_001378492.1	c.-279+2520A>G		intron_variant	Intron 2 of 8		NP_001365421.1
CLDN16	NM_001378493.1	c.-279+26988A>G		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.223+4405T>C		intron_variant	Intron 1 of 3	1	NM_021101.5	ENSP00000295522.3
P3H2-AS1	ENST00000747181.1	n.793+2520A>G		intron_variant	Intron 6 of 6

Frequencies

GnomAD3 genomes AF: 0.0455 AC: 6919 AN: 152184 Hom.: 268 Cov.: 32

Gnomad AFR AF: 0.0978

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0230

Gnomad ASJ AF: 0.0320

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0993

Gnomad FIN AF: 0.0234

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0235

Gnomad OTH AF: 0.0330

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

GnomAD4 genome AF: 0.0456 AC: 6940 AN: 152302 Hom.: 269 Cov.: 32 AF XY: 0.0456 AC XY: 3393 AN XY: 74480

African (AFR) AF: 0.0979 AC: 4066 AN: 41546

American (AMR) AF: 0.0230 AC: 352 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0320 AC: 111 AN: 3472

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5184

South Asian (SAS) AF: 0.0995 AC: 480 AN: 4822

European-Finnish (FIN) AF: 0.0234 AC: 249 AN: 10624

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0235 AC: 1596 AN: 68030

Other (OTH) AF: 0.0341 AC: 72 AN: 2112

Alfa AF: 0.0319 Hom.: 56

Bravo AF: 0.0457

Asia WGS AF: 0.0670 AC: 233 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.6
DANN	Benign	0.72
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: rs11717803; hg19: chr3-190035368;