16-61817615-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000577390.6(CDH8):​c.1141G>A​(p.Val381Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000651 in 1,613,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

CDH8
ENST00000577390.6 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.37
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.11129409).
BS2
High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CDH8NM_001796.5 linkuse as main transcriptc.1141G>A p.Val381Met missense_variant 7/12 ENST00000577390.6 NP_001787.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CDH8ENST00000577390.6 linkuse as main transcriptc.1141G>A p.Val381Met missense_variant 7/121 NM_001796.5 ENSP00000462701 P1

Frequencies

GnomAD3 genomes
AF:
0.000125
AC:
19
AN:
152030
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000338
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000194
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000557
AC:
14
AN:
251212
Hom.:
0
AF XY:
0.0000442
AC XY:
6
AN XY:
135766
show subpopulations
Gnomad AFR exome
AF:
0.000492
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000463
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000595
AC:
87
AN:
1461798
Hom.:
0
Cov.:
32
AF XY:
0.0000440
AC XY:
32
AN XY:
727188
show subpopulations
Gnomad4 AFR exome
AF:
0.000717
Gnomad4 AMR exome
AF:
0.0000895
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000459
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000118
AC:
18
AN:
152148
Hom.:
0
Cov.:
32
AF XY:
0.000134
AC XY:
10
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.000313
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000195
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000133
Hom.:
0
Bravo
AF:
0.000178
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000659
AC:
8
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

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 submitterclinical testingAmbry GeneticsSep 17, 2021The c.1141G>A (p.V381M) alteration is located in exon 7 (coding exon 6) of the CDH8 gene. This alteration results from a G to A substitution at nucleotide position 1141, causing the valine (V) at amino acid position 381 to be replaced by a methionine (M). 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
0.080
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
20
DANN
Uncertain
0.99
DEOGEN2
Benign
0.010
T;T;T;T;T
Eigen
Benign
0.027
Eigen_PC
Benign
0.11
FATHMM_MKL
Benign
0.35
N
LIST_S2
Uncertain
0.88
D;D;D;D;D
M_CAP
Benign
0.0086
T
MetaRNN
Benign
0.11
T;T;T;T;T
MetaSVM
Benign
-0.81
T
MutationAssessor
Benign
0.81
.;L;.;.;.
MutationTaster
Benign
0.90
D;D;D;D
PrimateAI
Uncertain
0.75
T
PROVEAN
Benign
-0.67
.;.;N;.;.
REVEL
Benign
0.13
Sift
Benign
0.14
.;.;T;.;.
Sift4G
Benign
0.20
T;T;T;T;.
Polyphen
0.23
.;B;.;.;.
Vest4
0.64
MVP
0.39
MPC
1.1
ClinPred
0.10
T
GERP RS
6.2
Varity_R
0.067
gMVP
0.34

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.

Other links and lift over

dbSNP: rs375557193; hg19: chr16-61851519; COSMIC: COSV54866609; API