16-61654011-C-T

Position:

chr16-61654011-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000577390.6(CDH8):c.1997G>A(p.Arg666His) variant causes a missense change. The variant allele was found at a frequency of 0.00153 in 1,613,362 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R666C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 3 hom. )

Consequence

CDH8
ENST00000577390.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.13

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05102372).

BS2

High AC in GnomAd4 at 169 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH8	NM_001796.5 linkuse as main transcript	c.1997G>A	p.Arg666His	missense_variant	12/12	ENST00000577390.6	NP_001787.2
CDH8	XM_005255760.5 linkuse as main transcript	c.1997G>A	p.Arg666His	missense_variant	12/13		XP_005255817.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CDH8	ENST00000577390.6 linkuse as main transcript	c.1997G>A	p.Arg666His	missense_variant	12/12	1	NM_001796.5	ENSP00000462701	P1
CDH8	ENST00000299345.10 linkuse as main transcript	c.1997G>A	p.Arg666His	missense_variant	12/13	5		ENSP00000299345
CDH8	ENST00000577730.5 linkuse as main transcript	c.1997G>A	p.Arg666His	missense_variant	11/12	5		ENSP00000462018
CDH8	ENST00000585315.5 linkuse as main transcript	c.*444G>A		3_prime_UTR_variant, NMD_transcript_variant	11/11	5		ENSP00000463266

Frequencies

GnomAD3 genomes

AF:

0.00111

AC:

169

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.000378

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00210

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000994

AC:

250

AN:

251406

Hom.:

AF XY:

0.00102

AC XY:

139

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00200

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.00158

AC:

2304

AN:

1461180

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

1118

AN XY:

726946

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.000300

Gnomad4 NFE exome

AF:

0.00199

Gnomad4 OTH exome

AF:

0.000928

GnomAD4 genome

AF:

0.00111

AC:

169

AN:

152182

Hom.:

Cov.:

AF XY:

0.00112

AC XY:

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.000378

Gnomad4 NFE

AF:

0.00210

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00156

Hom.:

Bravo

AF:

0.000990

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.000914

AC:

111

EpiCase

AF:

0.00158

EpiControl

AF:

0.000948

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 17, 2024

The c.1997G>A (p.R666H) alteration is located in exon 12 (coding exon 11) of the CDH8 gene. This alteration results from a G to A substitution at nucleotide position 1997, causing the arginine (R) at amino acid position 666 to be replaced by a histidine (H). 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

Uncertain

0.47

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.020

T;T;T

Eigen

Uncertain

0.61

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Benign

0.041

MetaRNN

Benign

0.051

T;T;T

MetaSVM

Uncertain

-0.15

MutationAssessor

Benign

0.44

.;N;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.1

.;.;N

REVEL

Uncertain

0.41

Sift

Benign

0.21

.;.;T

Sift4G

Benign

0.25

T;T;T

Polyphen

1.0

.;D;.

Vest4

0.70

MVP

0.80

MPC

1.5

ClinPred

0.045

GERP RS

5.7

Varity_R

0.15

gMVP

0.76

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