rs140846629

chr3-190312890-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PP3_Moderate BP6_Very_Strong 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. Variant has been reported in ClinVar as Likely benign (★★). 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:3
• Conservation: PhyloP100: 0.409

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:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PP3: Splicing scoreres supports a deletorius 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 [Likely_benign]. Clinvar id is 261404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-190312890-C-T is described in Lovd as [Likely_benign]. Variant chr3-190312890-C-T is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLDN1	NM_021101.5	c.370G>A	p.Ala124Thr	missense_variant	2/4	ENST00000295522.4
CLDN16	NM_001378492.1	c.-445-2003C>T		intron_variant
CLDN16	NM_001378493.1	c.-279+22299C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLDN1	ENST00000295522.4	c.370G>A	p.Ala124Thr	missense_variant	2/4	1	NM_021101.5	P1
CLDN1	ENST00000490800.1	n.329G>A		non_coding_transcript_exon_variant	1/2	2

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

GnomAD3 exomes AF: 0.00422 AC: 1061 AN: 251422 Hom.: 9 AF XY: 0.00399 AC XY: 542 AN XY: 135870

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 SAS exome AF: 0.00137

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

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00145

Gnomad4 FIN exome AF: 0.0248

Gnomad4 NFE exome AF: 0.00278

Gnomad4 OTH exome AF: 0.00280

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

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0262

Gnomad4 NFE AF: 0.00387

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00248 Hom.: 4

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	CLDN1: PP3, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	N
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

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

Publications

LitVar

Other links and lift over

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