3-190312891-A-G

Variant names:

• chr3-190312891-A-G
• rs9869263
• NM_021101.5:c.369T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_021101.5(CLDN1):​c.369T>C​(p.Gly123Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.838 in 1,613,742 control chromosomes in the GnomAD database, including 567,397 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (51537 hom., cov: 31)
  • Exomes 𝑓: 0.84 (515860 hom.)
• Consequence: CLDN1 NM_021101.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -7.62
• Publications: 29 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 3-190312891-A-G is Benign according to our data. Variant chr3-190312891-A-G is described in ClinVar as Benign. ClinVar VariationId is 195367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-7.62 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.839 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.369T>C	p.Gly123Gly	synonymous	Exon 2 of 4	NP_066924.1
	CLDN16	NM_001378492.1		c.-445-2002A>G		intron	N/A	NP_001365421.1
	CLDN16	NM_001378493.1		c.-279+22300A>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.369T>C	p.Gly123Gly	synonymous	Exon 2 of 4	ENSP00000295522.3
	CLDN1	ENST00000490800.1	TSL:2	n.328T>C		non_coding_transcript_exon	Exon 1 of 2
	P3H2-AS1	ENST00000747181.1		n.627-2002A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.823 AC: 125001 AN: 151954 Hom.: 51503 Cov.: 31

Gnomad AFR AF: 0.770

Gnomad AMI AF: 0.814

Gnomad AMR AF: 0.811

Gnomad ASJ AF: 0.862

Gnomad EAS AF: 0.833

Gnomad SAS AF: 0.827

Gnomad FIN AF: 0.879

Gnomad MID AF: 0.927

Gnomad NFE AF: 0.845

Gnomad OTH AF: 0.823

GnomAD2 exomes AF: 0.832 AC: 209149 AN: 251432 AF XY: 0.836

Gnomad AFR exome AF: 0.769

Gnomad AMR exome AF: 0.784

Gnomad ASJ exome AF: 0.864

Gnomad EAS exome AF: 0.823

Gnomad FIN exome AF: 0.869

Gnomad NFE exome AF: 0.848

Gnomad OTH exome AF: 0.839

GnomAD4 exome AF: 0.840 AC: 1227389 AN: 1461670 Hom.: 515860 Cov.: 52 AF XY: 0.840 AC XY: 610604 AN XY: 727148

African (AFR) AF: 0.769 AC: 25724 AN: 33464

American (AMR) AF: 0.783 AC: 34991 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.866 AC: 22639 AN: 26132

East Asian (EAS) AF: 0.850 AC: 33760 AN: 39698

South Asian (SAS) AF: 0.822 AC: 70925 AN: 86252

European-Finnish (FIN) AF: 0.871 AC: 46524 AN: 53408

Middle Eastern (MID) AF: 0.862 AC: 4972 AN: 5768

European-Non Finnish (NFE) AF: 0.843 AC: 937253 AN: 1111846

Other (OTH) AF: 0.838 AC: 50601 AN: 60388

GnomAD4 genome AF: 0.823 AC: 125089 AN: 152072 Hom.: 51537 Cov.: 31 AF XY: 0.825 AC XY: 61361 AN XY: 74346

African (AFR) AF: 0.770 AC: 31912 AN: 41450

American (AMR) AF: 0.811 AC: 12387 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.862 AC: 2992 AN: 3470

East Asian (EAS) AF: 0.833 AC: 4301 AN: 5162

South Asian (SAS) AF: 0.828 AC: 3984 AN: 4814

European-Finnish (FIN) AF: 0.879 AC: 9312 AN: 10596

Middle Eastern (MID) AF: 0.922 AC: 271 AN: 294

European-Non Finnish (NFE) AF: 0.845 AC: 57461 AN: 67988

Other (OTH) AF: 0.818 AC: 1727 AN: 2112

Alfa AF: 0.836 Hom.: 154884

Bravo AF: 0.814

Asia WGS AF: 0.800 AC: 2785 AN: 3478

EpiCase AF: 0.846

EpiControl AF: 0.851

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 19, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Neonatal ichthyosis-sclerosing cholangitis syndrome Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.037
DANN	Benign	0.72
PhyloP100		-7.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs9869263; hg19: chr3-190030680; COSMIC: COSV108084878;