Genetic Variant CDH12:p.Val68Met (chr5-22078475-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004061.5(CDH12):c.202G>A(p.Val68Met) variant causes a missense change. The variant allele was found at a frequency of 0.273 in 1,613,098 control chromosomes in the GnomAD database, including 66,303 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.36 ( 11877 hom., cov: 32)

Exomes 𝑓: 0.26 ( 54426 hom. )

Consequence

CDH12
NM_004061.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.78

Variant links:

Genes affected

CDH12 (HGNC:1751): (cadherin 12) This gene encodes a type II classical cadherin of the cadherin superfamily. Alternative splicing of this gene results in multiple transcript variants. At least one of these variants encodes a preproprotein that is proteolytically processed to generate the mature cadherin protein. These integral membrane proteins mediate calcium-dependent cell-cell adhesion and are composed of a large N-terminal extracellular domain, a single membrane-spanning domain, and a small, highly conserved C-terminal cytoplasmic domain. Type II (atypical) cadherins are defined based on their lack of a histidine-alanine-valine (HAV) cell adhesion recognition sequence specific to type I cadherins. This particular cadherin appears to be expressed specifically in the brain and its temporal pattern of expression would be consistent with a role during a critical period of neuronal development, perhaps specifically during synaptogenesis. [provided by RefSeq, Nov 2015]

CDH12 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.6773945E-5).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.615 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH12	NM_004061.5 link	c.202G>A	p.Val68Met	missense_variant	Exon 5 of 15	ENST00000382254.6	NP_004052.2	P55289-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH12	ENST00000382254.6 link	c.202G>A	p.Val68Met	missense_variant	Exon 5 of 15	1	NM_004061.5	ENSP00000371689.1		P55289-1

Frequencies

GnomAD3 genomes

AF:

0.358

AC:

54281

AN:

151788

Hom.:

11837

Cov.:

show subpopulations

Gnomad AFR

AF:

0.621

Gnomad AMI

AF:

0.161

Gnomad AMR

AF:

0.317

Gnomad ASJ

AF:

0.168

Gnomad EAS

AF:

0.150

Gnomad SAS

AF:

0.340

Gnomad FIN

AF:

0.291

Gnomad MID

AF:

0.218

Gnomad NFE

AF:

0.249

Gnomad OTH

AF:

0.305

GnomAD3 exomes

AF:

0.290

AC:

72793

AN:

251014

Hom.:

11991

AF XY:

0.286

AC XY:

38820

AN XY:

135634

show subpopulations

Gnomad AFR exome

AF:

0.637

Gnomad AMR exome

AF:

0.310

Gnomad ASJ exome

AF:

0.177

Gnomad EAS exome

AF:

0.144

Gnomad SAS exome

AF:

0.335

Gnomad FIN exome

AF:

0.291

Gnomad NFE exome

AF:

0.257

Gnomad OTH exome

AF:

0.252

GnomAD4 exome

AF:

0.264

AC:

386193

AN:

1461192

Hom.:

54426

Cov.:

AF XY:

0.266

AC XY:

193058

AN XY:

726938

show subpopulations

Gnomad4 AFR exome

AF:

0.637

Gnomad4 AMR exome

AF:

0.307

Gnomad4 ASJ exome

AF:

0.178

Gnomad4 EAS exome

AF:

0.172

Gnomad4 SAS exome

AF:

0.336

Gnomad4 FIN exome

AF:

0.291

Gnomad4 NFE exome

AF:

0.250

Gnomad4 OTH exome

AF:

0.262

GnomAD4 genome

AF:

0.358

AC:

54392

AN:

151906

Hom.:

11877

Cov.:

AF XY:

0.360

AC XY:

26688

AN XY:

74226

show subpopulations

Gnomad4 AFR

AF:

0.621

Gnomad4 AMR

AF:

0.317

Gnomad4 ASJ

AF:

0.168

Gnomad4 EAS

AF:

0.150

Gnomad4 SAS

AF:

0.341

Gnomad4 FIN

AF:

0.291

Gnomad4 NFE

AF:

0.249

Gnomad4 OTH

AF:

0.309

Alfa

AF:

0.263

Hom.:

14937

Bravo

AF:

0.365

TwinsUK

AF:

0.250

AC:

927

ALSPAC

AF:

0.245

AC:

946

ESP6500AA

AF:

0.620

AC:

2732

ESP6500EA

AF:

0.240

AC:

2068

ExAC

AF:

0.298

AC:

36245

Asia WGS

AF:

0.280

AC:

975

AN:

3476

EpiCase

AF:

0.250

EpiControl

AF:

0.254

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0084

T;T;.

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.63

.;T;T

MetaRNN

Benign

0.000037

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.70

N;N;N

PrimateAI

Uncertain

0.67

PROVEAN

Benign

0.71

N;N;N

REVEL

Benign

0.25

Sift

Benign

0.45

T;T;T

Sift4G

Benign

0.21

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.13

MPC

0.25

ClinPred

0.016

GERP RS

5.5

Varity_R

0.11

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over