16-61713919-T-G

Position:

chr16-61713919-T-G

Variant summary

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

The NM_001796.5(CDH8):c.1576A>C(p.Lys526Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000646 in 1,609,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

CDH8
NM_001796.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.37

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]

CDH8 links:

CDH8 (HGNC:):

CDH8 links:

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=0.10672909).

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH8	NM_001796.5 linkuse as main transcript	c.1576A>C	p.Lys526Gln	missense_variant	10/12	ENST00000577390.6	NP_001787.2	P55286
CDH8	XM_005255760.5 linkuse as main transcript	c.1576A>C	p.Lys526Gln	missense_variant	10/13		XP_005255817.1
CDH8	XM_047433482.1 linkuse as main transcript	c.1683A>C	p.Pro561Pro	synonymous_variant	11/12		XP_047289438.1
CDH8	XM_047433484.1 linkuse as main transcript	c.*23A>C		3_prime_UTR_variant	9/9		XP_047289440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH8	ENST00000577390.6 linkuse as main transcript	c.1576A>C	p.Lys526Gln	missense_variant	10/12	1	NM_001796.5	ENSP00000462701.1		P55286

Frequencies

GnomAD3 genomes

AF:

0.0000660

AC:

AN:

151622

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000718

AC:

AN:

250546

Hom.:

AF XY:

0.0000738

AC XY:

AN XY:

135414

show subpopulations

Gnomad AFR exome

AF:

0.0000619

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000645

AC:

AN:

1457896

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

725374

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000712

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000659

AC:

AN:

151740

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74184

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000132

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000100

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000741

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

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

Aug 02, 2022

The c.1576A>C (p.K526Q) alteration is located in exon 10 (coding exon 9) of the CDH8 gene. This alteration results from a A to C substitution at nucleotide position 1576, causing the lysine (K) at amino acid position 526 to be replaced by a glutamine (Q). 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

0.097

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.0042

T;T;T

Eigen

Benign

-0.23

Eigen_PC

Benign

0.041

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.73

T;T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.36

.;N;.

PrimateAI

Benign

0.47

PROVEAN

Benign

0.32

.;.;N

REVEL

Benign

0.053

Sift

Benign

0.52

.;.;T

Sift4G

Benign

0.68

T;T;T

Polyphen

0.0020

.;B;.

Vest4

0.26

MutPred

0.34

Loss of methylation at K526 (P = 0.0017);Loss of methylation at K526 (P = 0.0017);Loss of methylation at K526 (P = 0.0017);

MVP

0.60

MPC

0.51

ClinPred

0.070

GERP RS

6.1

Varity_R

0.17

gMVP

0.23

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