16-66386827-C-T

Variant names:

• chr16-66386827-C-T
• rs1342694698
• NM_001795.5:c.229C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001795.5(CDH5):​c.229C>T​(p.Arg77Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000096 in 1,458,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: CDH5 NM_001795.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0300
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25211805).
• BS2: High AC in GnomAdExome4 at 14 AD gene.

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.229C>T	p.Arg77Cys	missense	Exon 3 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.229C>T	p.Arg77Cys	missense	Exon 3 of 12	ENSP00000344115.3	P33151-1
	CDH5	ENST00000649567.1		c.229C>T	p.Arg77Cys	missense	Exon 4 of 13	ENSP00000497290.1	P33151-1
	CDH5	ENST00000894863.1		c.229C>T	p.Arg77Cys	missense	Exon 4 of 13	ENSP00000564922.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000202 AC: 5 AN: 247960 AF XY: 0.0000224

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000878

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000960 AC: 14 AN: 1458696 Hom.: 0 Cov.: 31 AF XY: 0.00000965 AC XY: 7 AN XY: 725118

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.0000675 AC: 3 AN: 44422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39586

South Asian (SAS) AF: 0.00 AC: 0 AN: 85870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53316

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

European-Non Finnish (NFE) AF: 0.00000811 AC: 9 AN: 1109906

Other (OTH) AF: 0.0000166 AC: 1 AN: 60310

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.016
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.20	N
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.030
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Benign	0.21
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.025	D
Polyphen		1.0	D
Vest4		0.39
MutPred		0.47		Loss of disorder (P = 0.0084)
MVP		0.52
MPC		0.70
ClinPred		0.62	D
GERP RS		-1.8
Varity_R		0.43
gMVP		0.48
Mutation Taster		=95/5	polymorphism

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: rs1342694698; hg19: chr16-66420730;