22-19524092-A-G

Variant names:

• chr22-19524092-A-G
• rs1934172728
• NM_001363066.2:c.164T>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001363066.2(CLDN5):​c.164T>C​(p.Val55Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CLDN5 NM_001363066.2 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.37

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41876164).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN5	NM_001363066.2	c.164T>C	p.Val55Ala	missense_variant	Exon 1 of 1	ENST00000618236.2	NP_001349995.1
CLDN5	NM_001130861.1	c.419T>C	p.Val140Ala	missense_variant	Exon 1 of 1		NP_001124333.1
CLDN5	NM_001363067.2	c.419T>C	p.Val140Ala	missense_variant	Exon 2 of 2		NP_001349996.1
CLDN5	NM_003277.4	c.419T>C	p.Val140Ala	missense_variant	Exon 2 of 2		NP_003268.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN5	ENST00000618236.2	c.164T>C	p.Val55Ala	missense_variant	Exon 1 of 1	6	NM_001363066.2	ENSP00000480623.1
CLDN5	ENST00000403084.1	c.419T>C	p.Val140Ala	missense_variant	Exon 1 of 1	6		ENSP00000384554.1
CLDN5	ENST00000406028.1	c.419T>C	p.Val140Ala	missense_variant	Exon 2 of 2	2		ENSP00000385477.1
CLDN5	ENST00000413119.2	c.419T>C	p.Val140Ala	missense_variant	Exon 2 of 2	2		ENSP00000400612.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Neurodevelopmental abnormality Uncertain:1

Apr 03, 2020

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;D;D;D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.91	.;D;.;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.42	T;T;T;T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	1.4	.;L;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.8	D;.;D;D
REVEL	Uncertain	0.60
Sift	Benign	0.088	T;.;T;T
Sift4G	Benign	0.097	T;T;T;T
Polyphen		0.88	P;.;P;P
Vest4		0.18
MutPred		0.52		Loss of helix (P = 0.1299);.;Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP		0.39
MPC		2.1
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.25
gMVP		0.79

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: rs1934172728; hg19: chr22-19511615;