22-19523532-C-A

Variant names:

• chr22-19523532-C-A
• rs756654
• NM_001363066.2:c.*67G>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001363066.2(CLDN5):​c.*67G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 1,484,968 control chromosomes in the GnomAD database, including 15,172 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1957 hom., cov: 34)
  • Exomes 𝑓: 0.14 (13215 hom.)
• Consequence: CLDN5 NM_001363066.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.104

Genes affected

CLDN5 (HGNC:2047): (claudin 5) 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. Mutations in this gene have been found in patients with velocardiofacial syndrome. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, May 2018]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 22-19523532-C-A is Benign according to our data. Variant chr22-19523532-C-A is described in ClinVar as [Benign]. Clinvar id is 1224832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN5	NM_001363066.2	c.*67G>T		3_prime_UTR_variant	Exon 1 of 1	ENST00000618236.2	NP_001349995.1
CLDN5	NM_001130861.1	c.*67G>T		3_prime_UTR_variant	Exon 1 of 1		NP_001124333.1
CLDN5	NM_001363067.2	c.*67G>T		3_prime_UTR_variant	Exon 2 of 2		NP_001349996.1
CLDN5	NM_003277.4	c.*67G>T		3_prime_UTR_variant	Exon 2 of 2		NP_003268.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN5	ENST00000618236	c.*67G>T		3_prime_UTR_variant	Exon 1 of 1		NM_001363066.2	ENSP00000480623.1
CLDN5	ENST00000403084	c.*67G>T		3_prime_UTR_variant	Exon 1 of 1			ENSP00000384554.1
CLDN5	ENST00000406028	c.*67G>T		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000385477.1
CLDN5	ENST00000413119	c.*67G>T		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000400612.2

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23229 AN: 152110 Hom.: 1958 Cov.: 34

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.205

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.142

GnomAD4 exome AF: 0.136 AC: 181610 AN: 1332740 Hom.: 13215 Cov.: 30 AF XY: 0.136 AC XY: 89013 AN XY: 652400

Gnomad4 AFR exome AF: 0.178

Gnomad4 AMR exome AF: 0.168

Gnomad4 ASJ exome AF: 0.115

Gnomad4 EAS exome AF: 0.313

Gnomad4 SAS exome AF: 0.132

Gnomad4 FIN exome AF: 0.145

Gnomad4 NFE exome AF: 0.128

Gnomad4 OTH exome AF: 0.138

GnomAD4 genome AF: 0.153 AC: 23232 AN: 152228 Hom.: 1957 Cov.: 34 AF XY: 0.154 AC XY: 11432 AN XY: 74444

Gnomad4 AFR AF: 0.177

Gnomad4 AMR AF: 0.141

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.310

Gnomad4 SAS AF: 0.133

Gnomad4 FIN AF: 0.144

Gnomad4 NFE AF: 0.133

Gnomad4 OTH AF: 0.140

Alfa AF: 0.116 Hom.: 362

Bravo AF: 0.157

Asia WGS AF: 0.197 AC: 682 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	5.5
DANN	Benign	0.81

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: rs756654; hg19: chr22-19511055; COSMIC: COSV99596534; COSMIC: COSV99596534;