Genetic Variant CDH8:p.Arg666Cys (chr16-61654012-G-A) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001796.5(CDH8):c.1996C>T(p.Arg666Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00314 in 1,613,080 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0033 ( 11 hom. )

Consequence

CDH8
NM_001796.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 5.60

Variant links:

Genes affected

CDH8 (HGNC:1767): (cadherin 8) This gene encodes a type II classical cadherin from the cadherin superfamily, integral membrane proteins that mediate calcium-dependent cell-cell adhesion. Mature cadherin proteins are composed of a large N-terminal extracellular domain, a single membrane-spanning domain, and a small, highly conserved C-terminal cytoplasmic domain. The extracellular domain consists of 5 subdomains, each containing a cadherin motif, and appears to determine the specificity of the protein's homophilic cell adhesion activity. Type II (atypical) cadherins are defined based on their lack of a HAV cell adhesion recognition sequence specific to type I cadherins. This particular cadherin is expressed in brain and is putatively involved in synaptic adhesion, axon outgrowth and guidance. [provided by RefSeq, Jul 2008]

CDH8 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.024894834).

BP6

Variant 16-61654012-G-A is Benign according to our data. Variant chr16-61654012-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 710638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 310 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH8	NM_001796.5 link	c.1996C>T	p.Arg666Cys	missense_variant	Exon 12 of 12	ENST00000577390.6	NP_001787.2	P55286
CDH8	XM_005255760.5 link	c.1996C>T	p.Arg666Cys	missense_variant	Exon 12 of 13		XP_005255817.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH8	ENST00000577390.6 link	c.1996C>T	p.Arg666Cys	missense_variant	Exon 12 of 12	1	NM_001796.5	ENSP00000462701.1		P55286

Frequencies

GnomAD3 genomes

AF:

0.00204

AC:

310

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000942

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00363

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.00193

AC:

485

AN:

251388

Hom.:

AF XY:

0.00183

AC XY:

249

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.000739

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000878

Gnomad NFE exome

AF:

0.00362

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00325

AC:

4749

AN:

1460910

Hom.:

Cov.:

AF XY:

0.00324

AC XY:

2352

AN XY:

726844

show subpopulations

Gnomad4 AFR exome

AF:

0.000598

Gnomad4 AMR exome

AF:

0.000559

Gnomad4 ASJ exome

AF:

0.00115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00110

Gnomad4 NFE exome

AF:

0.00405

Gnomad4 OTH exome

AF:

0.00182

GnomAD4 genome

AF:

0.00204

AC:

310

AN:

152170

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

120

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.000939

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.00363

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.00308

Hom.:

Bravo

AF:

0.00191

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00279

AC:

ExAC

AF:

0.00190

AC:

231

EpiCase

AF:

0.00273

EpiControl

AF:

0.00314

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.043

T;T;T

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.059

MetaRNN

Benign

0.025

T;T;T

MetaSVM

Uncertain

0.038

MutationAssessor

Benign

0.65

.;N;.

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-2.8

.;.;D

REVEL

Uncertain

0.56

Sift

Uncertain

0.029

.;.;D

Sift4G

Benign

0.11

T;T;T

Polyphen

1.0

.;D;.

Vest4

0.82

MVP

0.84

MPC

1.6

ClinPred

0.044

GERP RS

5.7

Varity_R

0.27

gMVP

0.88

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over