rs17429833

Variant names:

• chr3-190322219-C-G
• rs17429833
• NM_021101.5:c.-13G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021101.5(CLDN1):​c.-13G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0797 in 1,612,174 control chromosomes in the GnomAD database, including 5,555 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (385 hom., cov: 33)
  • Exomes 𝑓: 0.081 (5170 hom.)
• Consequence: CLDN1 NM_021101.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.154
• Publications: 12 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]

CLDN16 Gene-Disease associations (from GenCC):

• renal hypomagnesemia 3

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 3-190322219-C-G is Benign according to our data. Variant chr3-190322219-C-G is described in ClinVar as Benign. ClinVar VariationId is 261401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0849 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.-13G>C		5_prime_UTR	Exon 1 of 4	NP_066924.1
	CLDN16	NM_001378492.1		c.-279+7160C>G		intron	N/A	NP_001365421.1
	CLDN16	NM_001378493.1		c.-279+31628C>G		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.-13G>C		5_prime_UTR	Exon 1 of 4	ENSP00000295522.3

Frequencies

GnomAD3 genomes AF: 0.0659 AC: 10033 AN: 152194 Hom.: 386 Cov.: 33

Gnomad AFR AF: 0.0336

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0723

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.0143

Gnomad SAS AF: 0.0512

Gnomad FIN AF: 0.0929

Gnomad MID AF: 0.0605

Gnomad NFE AF: 0.0867

Gnomad OTH AF: 0.0779

GnomAD2 exomes AF: 0.0666 AC: 16468 AN: 247120 AF XY: 0.0685

Gnomad AFR exome AF: 0.0317

Gnomad AMR exome AF: 0.0471

Gnomad ASJ exome AF: 0.0382

Gnomad EAS exome AF: 0.0139

Gnomad FIN exome AF: 0.0928

Gnomad NFE exome AF: 0.0866

Gnomad OTH exome AF: 0.0803

GnomAD4 exome AF: 0.0811 AC: 118419 AN: 1459862 Hom.: 5170 Cov.: 31 AF XY: 0.0804 AC XY: 58384 AN XY: 726270

African (AFR) AF: 0.0322 AC: 1076 AN: 33440

American (AMR) AF: 0.0511 AC: 2283 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.0348 AC: 908 AN: 26112

East Asian (EAS) AF: 0.00995 AC: 395 AN: 39692

South Asian (SAS) AF: 0.0533 AC: 4595 AN: 86198

European-Finnish (FIN) AF: 0.0890 AC: 4712 AN: 52952

Middle Eastern (MID) AF: 0.0683 AC: 356 AN: 5216

European-Non Finnish (NFE) AF: 0.0894 AC: 99403 AN: 1111290

Other (OTH) AF: 0.0778 AC: 4691 AN: 60278

GnomAD4 genome AF: 0.0659 AC: 10031 AN: 152312 Hom.: 385 Cov.: 33 AF XY: 0.0648 AC XY: 4827 AN XY: 74466

African (AFR) AF: 0.0335 AC: 1393 AN: 41586

American (AMR) AF: 0.0721 AC: 1104 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0323 AC: 112 AN: 3470

East Asian (EAS) AF: 0.0141 AC: 73 AN: 5162

South Asian (SAS) AF: 0.0512 AC: 247 AN: 4824

European-Finnish (FIN) AF: 0.0929 AC: 986 AN: 10618

Middle Eastern (MID) AF: 0.0651 AC: 19 AN: 292

European-Non Finnish (NFE) AF: 0.0867 AC: 5898 AN: 68024

Other (OTH) AF: 0.0781 AC: 165 AN: 2114

Alfa AF: 0.0713 Hom.: 86

Bravo AF: 0.0644

Asia WGS AF: 0.0490 AC: 171 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	16
DANN	Benign	0.85
PhyloP100		0.15
PromoterAI		0.038	Neutral
Mutation Taster		=299/1	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: rs17429833; hg19: chr3-190040008;