7-73769403-C-T

Variant names:

• chr7-73769403-C-T
• rs868906959
• NM_001306.4:c.647G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001306.4(CLDN3):​c.647G>A​(p.Arg216His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000346 in 1,446,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R216L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: CLDN3 NM_001306.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22556859).

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.647G>A	p.Arg216His	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.647G>A	p.Arg216His	missense	Exon 1 of 1	ENSP00000378577.2	O15551

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000431 AC: 1 AN: 232062 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000559

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000346 AC: 5 AN: 1446180 Hom.: 0 Cov.: 31 AF XY: 0.00000417 AC XY: 3 AN XY: 719840

African (AFR) AF: 0.00 AC: 0 AN: 33376

American (AMR) AF: 0.00 AC: 0 AN: 44082

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25926

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 85844

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40714

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1110688

Other (OTH) AF: 0.00 AC: 0 AN: 60138

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.039	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.23	T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.026	D
Sift4G	Benign	0.16	T
Polyphen		0.97	D
Vest4		0.16
MutPred		0.26		Gain of methylation at K217 (P = 0.124)
MVP		0.66
MPC		1.4
ClinPred		0.65	D
GERP RS		4.6
Varity_R		0.24
gMVP		0.29
Mutation Taster		=87/13	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: rs868906959; hg19: chr7-73183733; COSMIC: COSV67777470;