3-190307888-C-A

Position:

• chr3-190307888-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021101.5(CLDN1):​c.*389G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0584 in 164,672 control chromosomes in the GnomAD database, including 361 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 0.058 (331 hom., cov: 32)
  • Exomes 𝑓: 0.063 (30 hom.)
• Consequence: CLDN1 NM_021101.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.420

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0802 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLDN1	NM_021101.5	c.*389G>T		3_prime_UTR_variant	4/4	ENST00000295522.4	NP_066924.1
CLDN16	NM_001378492.1	c.-445-7005C>A		intron_variant			NP_001365421.1
CLDN16	NM_001378493.1	c.-279+17297C>A		intron_variant			NP_001365422.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLDN1	ENST00000295522	c.*389G>T		3_prime_UTR_variant	4/4	1	NM_021101.5	ENSP00000295522.3

Frequencies

GnomAD3 genomes AF: 0.0580 AC: 8811 AN: 151884 Hom.: 331 Cov.: 32

Gnomad AFR AF: 0.0150

Gnomad AMI AF: 0.0912

Gnomad AMR AF: 0.0651

Gnomad ASJ AF: 0.0880

Gnomad EAS AF: 0.00405

Gnomad SAS AF: 0.0565

Gnomad FIN AF: 0.0698

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0820

Gnomad OTH AF: 0.0854

GnomAD4 exome AF: 0.0632 AC: 801 AN: 12670 Hom.: 30 Cov.: 0 AF XY: 0.0640 AC XY: 452 AN XY: 7060

Gnomad4 AFR exome AF: 0.00893

Gnomad4 AMR exome AF: 0.0652

Gnomad4 ASJ exome AF: 0.100

Gnomad4 EAS exome AF: 0.00159

Gnomad4 SAS exome AF: 0.0497

Gnomad4 FIN exome AF: 0.0538

Gnomad4 NFE exome AF: 0.0714

Gnomad4 OTH exome AF: 0.0673

GnomAD4 genome AF: 0.0580 AC: 8812 AN: 152002 Hom.: 331 Cov.: 32 AF XY: 0.0569 AC XY: 4224 AN XY: 74290

Gnomad4 AFR AF: 0.0150

Gnomad4 AMR AF: 0.0650

Gnomad4 ASJ AF: 0.0880

Gnomad4 EAS AF: 0.00406

Gnomad4 SAS AF: 0.0567

Gnomad4 FIN AF: 0.0698

Gnomad4 NFE AF: 0.0820

Gnomad4 OTH AF: 0.0850

Alfa AF: 0.0726 Hom.: 95

Bravo AF: 0.0560

Asia WGS AF: 0.0250 AC: 91 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.7
DANN	Benign	0.58

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: rs55724972; hg19: chr3-190025677;