Variant 16-61820936-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000577390.6(CDH8):c.1013G>A(p.Arg338Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CDH8
ENST00000577390.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.71

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 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=0.2560265).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH8	NM_001796.5 linkuse as main transcript	c.1013G>A	p.Arg338Lys	missense_variant	6/12	ENST00000577390.6	NP_001787.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH8	ENST00000577390.6 linkuse as main transcript	c.1013G>A	p.Arg338Lys	missense_variant	6/12	1	NM_001796.5	ENSP00000462701	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1458408

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725454

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Dec 28, 2023

The c.1013G>A (p.R338K) alteration is located in exon 6 (coding exon 5) of the CDH8 gene. This alteration results from a G to A substitution at nucleotide position 1013, causing the arginine (R) at amino acid position 338 to be replaced by a lysine (K). 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

0.10

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.0046

T;T;T;T;T

Eigen

Benign

-0.14

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.87

D;D;D;D;D

M_CAP

Benign

0.044

MetaRNN

Benign

0.26

T;T;T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

0.11

.;N;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.58

PROVEAN

Benign

0.42

.;.;N;.;.

REVEL

Benign

0.23

Sift

Benign

0.41

.;.;T;.;.

Sift4G

Benign

0.43

T;T;T;T;.

Polyphen

0.0010

.;B;.;.;.

Vest4

0.27

MutPred

0.52

Gain of ubiquitination at R338 (P = 0.0369);Gain of ubiquitination at R338 (P = 0.0369);Gain of ubiquitination at R338 (P = 0.0369);Gain of ubiquitination at R338 (P = 0.0369);Gain of ubiquitination at R338 (P = 0.0369);

MVP

0.22

MPC

0.0055

ClinPred

0.64

GERP RS

6.2

Varity_R

0.39

gMVP

0.65

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over