8-8702439-C-A

Variant names:

• chr8-8702439-C-A
• rs752248803
• NM_194284.3:c.41C>A

Variant summary

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

The NM_194284.3(CLDN23):​c.41C>A​(p.Ala14Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,427,040 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A14V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CLDN23 NM_194284.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.39
• Publications: 0 publications found

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]

ENSG00000254367 (HGNC:):

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_194284.3. 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
	CLDN23	NM_194284.3	MANE Select	c.41C>A	p.Ala14Glu	missense	Exon 1 of 1	NP_919260.2	Q96B33

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN23	ENST00000519106.2	TSL:6 MANE Select	c.41C>A	p.Ala14Glu	missense	Exon 1 of 1	ENSP00000428780.1	Q96B33
	ENSG00000254367	ENST00000765578.1		n.660+21091G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1427040 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 707344

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31700

American (AMR) AF: 0.00 AC: 0 AN: 40554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24356

East Asian (EAS) AF: 0.00 AC: 0 AN: 38768

South Asian (SAS) AF: 0.00 AC: 0 AN: 82792

European-Finnish (FIN) AF: 0.0000203 AC: 1 AN: 49304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4490

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1096420

Other (OTH) AF: 0.00 AC: 0 AN: 58656

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.81	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.4
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.022	D
Polyphen		0.97	D
Vest4		0.38
MutPred		0.51		Loss of helix (P = 0.3949)
MVP		0.94
MPC		0.68
ClinPred		0.98	D
GERP RS		3.3
Varity_R		0.52
gMVP		0.82
Mutation Taster		=85/15	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: rs752248803; hg19: chr8-8559949;