16-66398520-T-C

Variant names:

• chr16-66398520-T-C
• rs1049970
• NM_001795.5:c.1550T>C

Variant summary

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

The NM_001795.5(CDH5):​c.1550T>C​(p.Ile517Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.695 in 1,597,870 control chromosomes in the GnomAD database, including 388,402 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.72 (39206 hom., cov: 33)
  • Exomes 𝑓: 0.69 (349196 hom.)
• Consequence: CDH5 NM_001795.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.10
• Publications: 47 publications found

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

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

• BP4: Computational evidence support a benign effect (MetaRNN=9.031497E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.789 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001795.5. 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
	CDH5	NM_001795.5	MANE Select	c.1550T>C	p.Ile517Thr	missense	Exon 10 of 12	NP_001786.2	P33151-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH5	ENST00000341529.8	TSL:1 MANE Select	c.1550T>C	p.Ile517Thr	missense	Exon 10 of 12	ENSP00000344115.3	P33151-1
	CDH5	ENST00000649567.1		c.1550T>C	p.Ile517Thr	missense	Exon 11 of 13	ENSP00000497290.1	P33151-1
	CDH5	ENST00000894863.1		c.1550T>C	p.Ile517Thr	missense	Exon 11 of 13	ENSP00000564922.1

Frequencies

GnomAD3 genomes AF: 0.716 AC: 108798 AN: 151882 Hom.: 39160 Cov.: 33

Gnomad AFR AF: 0.738

Gnomad AMI AF: 0.656

Gnomad AMR AF: 0.793

Gnomad ASJ AF: 0.700

Gnomad EAS AF: 0.808

Gnomad SAS AF: 0.690

Gnomad FIN AF: 0.666

Gnomad MID AF: 0.690

Gnomad NFE AF: 0.690

Gnomad OTH AF: 0.731

GnomAD2 exomes AF: 0.726 AC: 182273 AN: 251232 AF XY: 0.718

Gnomad AFR exome AF: 0.743

Gnomad AMR exome AF: 0.867

Gnomad ASJ exome AF: 0.707

Gnomad EAS exome AF: 0.800

Gnomad FIN exome AF: 0.671

Gnomad NFE exome AF: 0.691

Gnomad OTH exome AF: 0.717

GnomAD4 exome AF: 0.693 AC: 1001858 AN: 1445870 Hom.: 349196 Cov.: 30 AF XY: 0.693 AC XY: 499499 AN XY: 720326

African (AFR) AF: 0.733 AC: 24346 AN: 33222

American (AMR) AF: 0.857 AC: 38321 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.709 AC: 18455 AN: 26040

East Asian (EAS) AF: 0.800 AC: 31687 AN: 39632

South Asian (SAS) AF: 0.694 AC: 59616 AN: 85906

European-Finnish (FIN) AF: 0.670 AC: 35755 AN: 53362

Middle Eastern (MID) AF: 0.692 AC: 3962 AN: 5726

European-Non Finnish (NFE) AF: 0.682 AC: 748379 AN: 1097404

Other (OTH) AF: 0.690 AC: 41337 AN: 59882

GnomAD4 genome AF: 0.716 AC: 108898 AN: 152000 Hom.: 39206 Cov.: 33 AF XY: 0.716 AC XY: 53210 AN XY: 74290

African (AFR) AF: 0.738 AC: 30586 AN: 41444

American (AMR) AF: 0.793 AC: 12117 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.700 AC: 2427 AN: 3468

East Asian (EAS) AF: 0.809 AC: 4167 AN: 5150

South Asian (SAS) AF: 0.689 AC: 3318 AN: 4816

European-Finnish (FIN) AF: 0.666 AC: 7038 AN: 10568

Middle Eastern (MID) AF: 0.690 AC: 203 AN: 294

European-Non Finnish (NFE) AF: 0.690 AC: 46903 AN: 67958

Other (OTH) AF: 0.729 AC: 1542 AN: 2116

Alfa AF: 0.703 Hom.: 176818

Bravo AF: 0.728

ESP6500AA AF: 0.618 AC: 2722

ESP6500EA AF: 0.561 AC: 4823

ExAC AF: 0.721 AC: 87480

Asia WGS AF: 0.718 AC: 2494 AN: 3478

EpiCase AF: 0.695

EpiControl AF: 0.689

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	14
DANN	Benign	0.94
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.080	T
MetaRNN	Benign	9.0e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.42	N
PhyloP100		2.1
PrimateAI	Benign	0.26	T
PROVEAN	Benign	2.3	N
REVEL	Benign	0.10
Sift	Benign	0.10	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.050
MPC		0.21
ClinPred		0.0098	T
GERP RS		4.0
Varity_R		0.039
gMVP		0.094
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1049970; hg19: chr16-66432423; COSMIC: COSV58516010;