chr22-19523788-C-A

Variant names:

• chr22-19523788-C-A
• rs1479084723
• NM_001363066.2:c.468G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001363066.2(CLDN5):​c.468G>T​(p.Gln156His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,454,012 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CLDN5 NM_001363066.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.17
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.4376 (below the threshold of 3.09). Trascript score misZ: 1.274 (below the threshold of 3.09). GenCC associations: The gene is linked to neurodevelopmental disorder.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363066.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN5	NM_001363066.2	MANE Select	c.468G>T	p.Gln156His	missense	Exon 1 of 1	NP_001349995.1	O00501
	CLDN5	NM_001130861.1		c.723G>T	p.Gln241His	missense	Exon 1 of 1	NP_001124333.1	O00501
	CLDN5	NM_001363067.2		c.723G>T	p.Gln241His	missense	Exon 2 of 2	NP_001349996.1	D3DX19

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN5	ENST00000618236.2	TSL:6 MANE Select	c.468G>T	p.Gln156His	missense	Exon 1 of 1	ENSP00000480623.1	O00501
	CLDN5	ENST00000403084.1	TSL:6	c.723G>T	p.Gln241His	missense	Exon 1 of 1	ENSP00000384554.1	D3DX19
	CLDN5	ENST00000406028.1	TSL:2	c.723G>T	p.Gln241His	missense	Exon 2 of 2	ENSP00000385477.1	D3DX19

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1454012 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722814

African (AFR) AF: 0.00 AC: 0 AN: 33362

American (AMR) AF: 0.00 AC: 0 AN: 43550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25960

East Asian (EAS) AF: 0.00 AC: 0 AN: 39396

South Asian (SAS) AF: 0.00 AC: 0 AN: 85474

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1109056

Other (OTH) AF: 0.00 AC: 0 AN: 60062

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.30	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.2
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.64
Sift	Benign	0.048	D
Sift4G	Uncertain	0.049	D
Polyphen		0.90	P
Vest4		0.23
MutPred		0.56		Loss of catalytic residue at Q241 (P = 0.0848)
MVP		0.69
MPC		1.6
ClinPred		0.99	D
GERP RS		3.7
Varity_R		0.24
gMVP		0.74
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1479084723; hg19: chr22-19511311;