8-8702909-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_194284.3(CLDN23):c.511C>A(p.Leu171Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000706 in 1,417,210 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: CLDN23 NM_194284.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.307

Genes affected

CLDN23 (HGNC:17591): (claudin 23) This gene encodes a member of the claudin family. Claudins are integral membrane proteins and components of tight junction strands. Tight junction strands serve as a physical barrier to prevent solutes and water from passing freely through the paracellular space between epithelial or endothelial cell sheets, and also play critical roles in maintaining cell polarity and signal transductions. This gene is expressed in germinal center B-cells, placenta and stomach as well as in colon tumor. This gene is down-regulated in intestinal type gastric cancer. [provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLDN23	NM_194284.3	c.511C>A	p.Leu171Met	missense_variant	1/1	ENST00000519106.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLDN23	ENST00000519106.2	c.511C>A	p.Leu171Met	missense_variant	1/1		NM_194284.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.06e-7 AC: 1 AN: 1417210 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 700112

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000235

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2023

The c.511C>A (p.L171M) alteration is located in exon 1 (coding exon 1) of the CLDN23 gene. This alteration results from a C to A substitution at nucleotide position 511, causing the leucine (L) at amino acid position 171 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.082
FATHMM_MKL	Benign	0.54	D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Uncertain	0.0010	D
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	0.82	N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.85	N
REVEL	Uncertain	0.34
Sift	Benign	0.13	T
Sift4G	Uncertain	0.022	D
Polyphen		0.99	D
Vest4		0.38
MutPred		0.49		Loss of stability (P = 0.2275);
MVP		0.91
MPC		0.73
ClinPred		0.49	T
GERP RS		1.1
Varity_R		0.16
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1322843320; hg19: chr8-8560419;