chr22-19526475-G-C

Variant names:

• chr22-19526475-G-C
• rs739371
• ENST00000406028.1:c.-33+42C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000406028.1(CLDN5):​c.-33+42C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 980,238 control chromosomes in the GnomAD database, including 34,454 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.36 (12792 hom., cov: 33)
  • Exomes 𝑓: 0.22 (21662 hom.)
• Consequence: CLDN5 ENST00000406028.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.543
• Publications: 6 publications found

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]

CLDN5 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.648 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN5	ENST00000406028.1	c.-33+42C>G		intron_variant	Intron 1 of 1	2		ENSP00000385477.1

Frequencies

GnomAD3 genomes AF: 0.361 AC: 54846 AN: 151974 Hom.: 12767 Cov.: 33

Gnomad AFR AF: 0.654

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.341

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.481

Gnomad SAS AF: 0.275

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.333

GnomAD4 exome AF: 0.217 AC: 179896 AN: 828146 Hom.: 21662 Cov.: 17 AF XY: 0.217 AC XY: 82929 AN XY: 382636

African (AFR) AF: 0.700 AC: 10993 AN: 15694

American (AMR) AF: 0.327 AC: 322 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 1026 AN: 5130

East Asian (EAS) AF: 0.463 AC: 1664 AN: 3596

South Asian (SAS) AF: 0.254 AC: 4156 AN: 16374

European-Finnish (FIN) AF: 0.241 AC: 66 AN: 274

Middle Eastern (MID) AF: 0.291 AC: 469 AN: 1612

European-Non Finnish (NFE) AF: 0.204 AC: 154444 AN: 757346

Other (OTH) AF: 0.249 AC: 6756 AN: 27136

GnomAD4 genome AF: 0.361 AC: 54919 AN: 152092 Hom.: 12792 Cov.: 33 AF XY: 0.362 AC XY: 26897 AN XY: 74350

African (AFR) AF: 0.654 AC: 27133 AN: 41486

American (AMR) AF: 0.341 AC: 5214 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 662 AN: 3470

East Asian (EAS) AF: 0.481 AC: 2478 AN: 5154

South Asian (SAS) AF: 0.274 AC: 1324 AN: 4828

European-Finnish (FIN) AF: 0.242 AC: 2557 AN: 10572

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.214 AC: 14564 AN: 67984

Other (OTH) AF: 0.329 AC: 697 AN: 2116

Alfa AF: 0.301 Hom.: 1120

Bravo AF: 0.385

Asia WGS AF: 0.378 AC: 1315 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.2
DANN	Benign	0.45
PhyloP100		-0.54
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs739371; hg19: chr22-19513998;