13-95560153-G-A

Variant names:

• chr13-95560153-G-A
• rs1188481980
• NM_006984.5:c.242G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_006984.5(CLDN10):​c.242G>A​(p.Gly81Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,778 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: 6.8e-7 (0 hom.)
• Consequence: CLDN10 NM_006984.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.25

Genes affected

CLDN10 (HGNC:2033): (claudin 10) 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. The expression level of this gene is associated with recurrence of primary hepatocellular carcinoma. Six alternatively spliced transcript variants encoding different isoforms have been reported, but the transcript sequences of some variants are not determined.[provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a chain Claudin-10 (size 227) in uniprot entity CLD10_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_006984.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN10	NM_006984.5	c.242G>A	p.Gly81Glu	missense_variant	Exon 2 of 5	ENST00000299339.3	NP_008915.1
CLDN10	NM_182848.4	c.236G>A	p.Gly79Glu	missense_variant	Exon 2 of 5		NP_878268.1
CLDN10	NM_001160100.2	c.179G>A	p.Gly60Glu	missense_variant	Exon 2 of 5		NP_001153572.1
CLDN10	XM_047430765.1	c.68G>A	p.Gly23Glu	missense_variant	Exon 3 of 6		XP_047286721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN10	ENST00000299339.3	c.242G>A	p.Gly81Glu	missense_variant	Exon 2 of 5	1	NM_006984.5	ENSP00000299339.2
CLDN10	ENST00000376873.7	c.236G>A	p.Gly79Glu	missense_variant	Exon 2 of 5	2		ENSP00000366069.2
CLDN10	ENST00000376855	c.-5G>A		5_prime_UTR_variant	Exon 1 of 2	2		ENSP00000366051.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251338 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135828

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461778 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 05, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.242G>A (p.G81E) alteration is located in exon 2 (coding exon 2) of the CLDN10 gene. This alteration results from a G to A substitution at nucleotide position 242, causing the glycine (G) at amino acid position 81 to be replaced by a glutamic acid (E). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	.;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.3	.;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.0	D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	.;D
Vest4		0.90
MutPred		0.74		.;Gain of catalytic residue at A85 (P = 0.0042);
MVP		0.99
MPC		1.3
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.82
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1188481980; hg19: chr13-96212407; COSMIC: COSV100176321;