chr7-73769986-C-T

Variant names:

• chr7-73769986-C-T
• rs548624692
• NM_001306.4:c.64G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001306.4(CLDN3):​c.64G>A​(p.Val22Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,408 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V22L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CLDN3 NM_001306.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.14
• Publications: 0 publications found

Genes affected

CLDN3 (HGNC:2045): (claudin 3) 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 intronless gene, a member of the claudin family, is an integral membrane protein and a component of tight junction strands. It is also a low-affinity receptor for Clostridium perfringens enterotoxin, and shares aa sequence similarity with a putative apoptosis-related protein found in rat. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001306.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN3	NM_001306.4	MANE Select	c.64G>A	p.Val22Met	missense	Exon 1 of 1	NP_001297.1	Q75L79

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN3	ENST00000395145.3	TSL:6 MANE Select	c.64G>A	p.Val22Met	missense	Exon 1 of 1	ENSP00000378577.2	O15551

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000808 AC: 2 AN: 247490 AF XY: 0.00000744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460408 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726526

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5504

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111682

Other (OTH) AF: 0.00 AC: 0 AN: 60312

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	-0.049
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.075	N
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		-2.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.57
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.82	P
Vest4		0.15
MutPred		0.46		Gain of helix (P = 0.132)
MVP		0.86
MPC		1.2
ClinPred		0.98	D
GERP RS		0.56
PromoterAI		-0.0060	Neutral
Varity_R		0.19
gMVP		0.61
Mutation Taster		=94/6	polymorphism

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: rs548624692; hg19: chr7-73184316;