8-8702619-C-A

Variant names:

• chr8-8702619-C-A
• NM_194284.3:c.221C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_194284.3(CLDN23):​c.221C>A​(p.Ala74Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,452,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CLDN23 NM_194284.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.13

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.83

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN23	NM_194284.3	c.221C>A	p.Ala74Asp	missense_variant	Exon 1 of 1	ENST00000519106.2	NP_919260.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN23	ENST00000519106.2	c.221C>A	p.Ala74Asp	missense_variant	Exon 1 of 1	6	NM_194284.3	ENSP00000428780.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1452516 Hom.: 0 Cov.: 33 AF XY: 0.00000416 AC XY: 3 AN XY: 721660

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000181

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.221C>A (p.A74D) 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 221, causing the alanine (A) at amino acid position 74 to be replaced by an aspartic acid (D). 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	Uncertain	0.34
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.052	N
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.0	L
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.76	N
REVEL	Uncertain	0.39
Sift	Benign	0.64	T
Sift4G	Benign	0.31	T
Polyphen		0.68	P
Vest4		0.35
MutPred		0.80		Loss of phosphorylation at Y71 (P = 0.201);
MVP		0.76
MPC		0.32
ClinPred		0.18	T
GERP RS		4.8
Varity_R		0.15
gMVP		0.61

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-8560129;