rs12696600

Variant names:

• chr3-190322418-C-A
• rs12696600
• NM_021101.5:c.-212G>T

Your query was ambiguous. Multiple possible variants found:

• chr3-190322418-C-A
• chr3-190322418-C-G

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.-212G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.571 in 594,924 control chromosomes in the GnomAD database, including 99,434 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (28339 hom., cov: 34)
  • Exomes 𝑓: 0.56 (71095 hom.)
• Consequence: CLDN1 NM_021101.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.01
• Publications: 13 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=-0.69).
• BP6: Variant 3-190322418-C-A is Benign according to our data. Variant chr3-190322418-C-A is described in ClinVar as Benign. ClinVar VariationId is 1259600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.759 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN1	NM_021101.5	c.-212G>T		5_prime_UTR_variant	Exon 1 of 4	ENST00000295522.4	NP_066924.1
CLDN16	NM_001378492.1	c.-279+7359C>A		intron_variant	Intron 2 of 8		NP_001365421.1
CLDN16	NM_001378493.1	c.-279+31827C>A		intron_variant	Intron 1 of 7		NP_001365422.1
CLDN16	XM_047447333.1	c.-413C>A		upstream_gene_variant			XP_047303289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN1	ENST00000295522.4	c.-212G>T		5_prime_UTR_variant	Exon 1 of 4	1	NM_021101.5	ENSP00000295522.3
CLDN16	ENST00000468220.1	n.-123C>A		upstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.602 AC: 91471 AN: 151982 Hom.: 28318 Cov.: 34

Gnomad AFR AF: 0.745

Gnomad AMI AF: 0.646

Gnomad AMR AF: 0.573

Gnomad ASJ AF: 0.551

Gnomad EAS AF: 0.780

Gnomad SAS AF: 0.554

Gnomad FIN AF: 0.540

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.524

Gnomad OTH AF: 0.575

GnomAD4 exome AF: 0.561 AC: 248224 AN: 442824 Hom.: 71095 Cov.: 3 AF XY: 0.557 AC XY: 130024 AN XY: 233324

African (AFR) AF: 0.738 AC: 9130 AN: 12368

American (AMR) AF: 0.598 AC: 11448 AN: 19152

Ashkenazi Jewish (ASJ) AF: 0.564 AC: 7638 AN: 13540

East Asian (EAS) AF: 0.810 AC: 24855 AN: 30670

South Asian (SAS) AF: 0.550 AC: 25286 AN: 45936

European-Finnish (FIN) AF: 0.526 AC: 15085 AN: 28670

Middle Eastern (MID) AF: 0.565 AC: 1084 AN: 1920

European-Non Finnish (NFE) AF: 0.525 AC: 139117 AN: 265006

Other (OTH) AF: 0.570 AC: 14581 AN: 25562

GnomAD4 genome AF: 0.602 AC: 91536 AN: 152100 Hom.: 28339 Cov.: 34 AF XY: 0.602 AC XY: 44741 AN XY: 74342

African (AFR) AF: 0.744 AC: 30922 AN: 41540

American (AMR) AF: 0.573 AC: 8769 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.551 AC: 1912 AN: 3470

East Asian (EAS) AF: 0.779 AC: 3995 AN: 5128

South Asian (SAS) AF: 0.553 AC: 2665 AN: 4822

European-Finnish (FIN) AF: 0.540 AC: 5709 AN: 10580

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.524 AC: 35569 AN: 67944

Other (OTH) AF: 0.574 AC: 1212 AN: 2112

Alfa AF: 0.564 Hom.: 15134

Bravo AF: 0.615

Asia WGS AF: 0.678 AC: 2355 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	-0.69
CADD	Benign	6.8
DANN	Benign	0.81
PhyloP100		-1.0
PromoterAI		-0.081	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Mutation Taster		=298/2	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: rs12696600; hg19: chr3-190040207;