rs140846629

Variant names:

• chr3-190312890-C-T
• rs140846629
• NM_021101.5:c.370G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP3_Moderate BP6_Very_Strong BS1 BS2

The NM_021101.5(CLDN1):​c.370G>A​(p.Ala124Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00337 in 1,613,992 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A124V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0041 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (27 hom.)
• Consequence: CLDN1 NM_021101.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.409
• Publications: 8 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 -14 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 3-190312890-C-T is Benign according to our data. Variant chr3-190312890-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00409 (623/152218) while in subpopulation NFE AF = 0.00387 (263/68004). AF 95% confidence interval is 0.00348. There are 6 homozygotes in GnomAd4. There are 361 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.370G>A	p.Ala124Thr	missense	Exon 2 of 4	NP_066924.1
	CLDN16	NM_001378492.1		c.-445-2003C>T		intron	N/A	NP_001365421.1
	CLDN16	NM_001378493.1		c.-279+22299C>T		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.370G>A	p.Ala124Thr	missense	Exon 2 of 4	ENSP00000295522.3
	CLDN1	ENST00000490800.1	TSL:2	n.329G>A		non_coding_transcript_exon	Exon 1 of 2
	P3H2-AS1	ENST00000747181.1		n.627-2003C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00410 AC: 623 AN: 152100 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0262

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00387

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00422 AC: 1061 AN: 251422 AF XY: 0.00399

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0248

Gnomad NFE exome AF: 0.00342

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00329 AC: 4809 AN: 1461774 Hom.: 27 Cov.: 30 AF XY: 0.00324 AC XY: 2357 AN XY: 727194

African (AFR) AF: 0.000388 AC: 13 AN: 33474

American (AMR) AF: 0.00165 AC: 74 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00145 AC: 125 AN: 86254

European-Finnish (FIN) AF: 0.0248 AC: 1326 AN: 53412

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00278 AC: 3092 AN: 1111918

Other (OTH) AF: 0.00280 AC: 169 AN: 60394

GnomAD4 genome AF: 0.00409 AC: 623 AN: 152218 Hom.: 6 Cov.: 33 AF XY: 0.00485 AC XY: 361 AN XY: 74426

African (AFR) AF: 0.000626 AC: 26 AN: 41544

American (AMR) AF: 0.00262 AC: 40 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4822

European-Finnish (FIN) AF: 0.0262 AC: 277 AN: 10590

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00387 AC: 263 AN: 68004

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00156 Hom.: 6

Bravo AF: 0.00166

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00377 AC: 458

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00273

EpiControl AF: 0.00279

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

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

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CLDN1: PP3, BS2

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0079	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.41
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.20
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.54	P
Vest4		0.13
MVP		0.85
MPC		0.37
ClinPred		0.020	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.076
gMVP		0.37
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.85		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs140846629; hg19: chr3-190030679; COSMIC: COSV55043979;