chr16-66386949-C-A

Position:

• chr16-66386949-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001795.5(CDH5):​c.351C>A​(p.His117Gln) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH5 NM_001795.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.293

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.083644).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH5	NM_001795.5	c.351C>A	p.His117Gln	missense_variant	3/12	ENST00000341529.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH5	ENST00000341529.8	c.351C>A	p.His117Gln	missense_variant	3/12	1	NM_001795.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 2024

The c.351C>A (p.H117Q) alteration is located in exon 3 (coding exon 2) of the CDH5 gene. This alteration results from a C to A substitution at nucleotide position 351, causing the histidine (H) at amino acid position 117 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	1.2
DANN	Benign	0.76
DEOGEN2	Benign	0.089	.;T;T;T;T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.30	T;.;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.084	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.39	N;N;N;.;.
MutationTaster	Benign	0.61	D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.53	.;N;.;N;.
REVEL	Benign	0.030
Sift	Benign	0.12	.;T;.;T;.
Sift4G	Benign	0.36	T;T;.;T;T
Polyphen		0.0010	.;B;B;.;.
Vest4		0.13
MutPred		0.43		Loss of disorder (P = 0.169);Loss of disorder (P = 0.169);Loss of disorder (P = 0.169);Loss of disorder (P = 0.169);Loss of disorder (P = 0.169);
MVP		0.30
MPC		0.17
ClinPred		0.013	T
GERP RS		-0.14
Varity_R		0.084
gMVP		0.30

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-66420852;