13-95560139-A-C

Position:

• chr13-95560139-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_006984.5(CLDN10):​c.228A>C​(p.Ile76Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,612,620 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0089 (23 hom., cov: 33)
  • Exomes 𝑓: 0.00092 (20 hom.)
• Consequence: CLDN10 NM_006984.5 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.10

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 13-95560139-A-C is Benign according to our data. Variant chr13-95560139-A-C is described in ClinVar as [Benign]. Clinvar id is 3044485.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=1.1 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00888 (1353/152354) while in subpopulation AFR AF= 0.031 (1290/41584). AF 95% confidence interval is 0.0296. There are 23 homozygotes in gnomad4. There are 652 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLDN10	NM_006984.5	c.228A>C	p.Ile76Ile	synonymous_variant	2/5	ENST00000299339.3	NP_008915.1
CLDN10	NM_182848.4	c.222A>C	p.Ile74Ile	synonymous_variant	2/5		NP_878268.1
CLDN10	NM_001160100.2	c.165A>C	p.Ile55Ile	synonymous_variant	2/5		NP_001153572.1
CLDN10	XM_047430765.1	c.54A>C	p.Ile18Ile	synonymous_variant	3/6		XP_047286721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLDN10	ENST00000299339.3	c.228A>C	p.Ile76Ile	synonymous_variant	2/5	1	NM_006984.5	ENSP00000299339.2
CLDN10	ENST00000376873.7	c.222A>C	p.Ile74Ile	synonymous_variant	2/5	2		ENSP00000366069.2
CLDN10	ENST00000376855.1	c.-19A>C		upstream_gene_variant		2		ENSP00000366051.1

Frequencies

GnomAD3 genomes AF: 0.00883 AC: 1344 AN: 152236 Hom.: 23 Cov.: 33

Gnomad AFR AF: 0.0309

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00226 AC: 566 AN: 250698 Hom.: 5 AF XY: 0.00173 AC XY: 234 AN XY: 135456

Gnomad AFR exome AF: 0.0300

Gnomad AMR exome AF: 0.00169

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000921 AC: 1345 AN: 1460266 Hom.: 20 Cov.: 31 AF XY: 0.000819 AC XY: 595 AN XY: 726186

Gnomad4 AFR exome AF: 0.0319

Gnomad4 AMR exome AF: 0.00166

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000522

Gnomad4 OTH exome AF: 0.00214

GnomAD4 genome AF: 0.00888 AC: 1353 AN: 152354 Hom.: 23 Cov.: 33 AF XY: 0.00875 AC XY: 652 AN XY: 74506

Gnomad4 AFR AF: 0.0310

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00378 Hom.: 7

Bravo AF: 0.00958

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CLDN10-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 07, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	13
DANN	Benign	0.70

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

LitVar

Other links and lift over

dbSNP: rs34449921; hg19: chr13-96212393;