chr16-66386863-G-A

Position:

• chr16-66386863-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001795.5(CDH5):​c.265G>A​(p.Val89Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CDH5 NM_001795.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.38

Genes affected

CDH5 (HGNC:1764): (cadherin 5) This gene encodes a classical cadherin of the cadherin superfamily. The encoded preproprotein is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion molecule is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Functioning as a classical cadherin by imparting to cells the ability to adhere in a homophilic manner, this protein plays a role in endothelial adherens junction assembly and maintenance. This gene is located in a gene cluster in a region on the long arm of chromosome 16 that is involved in loss of heterozygosity events in breast and prostate cancer. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH5	NM_001795.5	c.265G>A	p.Val89Met	missense_variant	3/12	ENST00000341529.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH5	ENST00000341529.8	c.265G>A	p.Val89Met	missense_variant	3/12	1	NM_001795.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461846 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Marfanoid habitus and intellectual disability Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	.;T;T;T;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.81	T;.;T;T;T
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.1	M;M;M;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.0	.;N;.;N;.
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	.;D;.;D;.
Sift4G	Uncertain	0.0020	D;D;.;D;D
Polyphen		0.88	.;P;P;.;.
Vest4		0.18
MutPred		0.75		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.66
MPC		0.55
ClinPred		0.88	D
GERP RS		5.9
Varity_R		0.40
gMVP		0.60

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: rs1596937199; hg19: chr16-66420766;