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

Variant summary

Our verdict is Benign. The variant received -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. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

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

Publications

30 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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

GnomAD2 exomes

AF:

0.290

AC:

72793

AN:

251014

AF XY:

0.286

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 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

African (AFR)

AF:

0.637

AC:

21317

AN:

33448

American (AMR)

AF:

0.307

AC:

13737

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.178

AC:

4655

AN:

26122

East Asian (EAS)

AF:

0.172

AC:

6830

AN:

39680

South Asian (SAS)

AF:

0.336

AC:

29001

AN:

86240

European-Finnish (FIN)

AF:

0.291

AC:

15519

AN:

53410

Middle Eastern (MID)

AF:

0.234

AC:

1348

AN:

5766

European-Non Finnish (NFE)

AF:

0.250

AC:

277979

AN:

1111458

Other (OTH)

AF:

0.262

AC:

15807

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

14826

29652

44477

59303

74129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9562

19124

28686

38248

47810

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.358

AC:

54392

AN:

151906

Hom.:

11877

Cov.:

AF XY:

0.360

AC XY:

26688

AN XY:

74226

show subpopulations

African (AFR)

AF:

0.621

AC:

25707

AN:

41388

American (AMR)

AF:

0.317

AC:

4824

AN:

15232

Ashkenazi Jewish (ASJ)

AF:

0.168

AC:

582

AN:

3470

East Asian (EAS)

AF:

0.150

AC:

772

AN:

5154

South Asian (SAS)

AF:

0.341

AC:

1640

AN:

4816

European-Finnish (FIN)

AF:

0.291

AC:

3072

AN:

10552

Middle Eastern (MID)

AF:

0.214

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.249

AC:

16934

AN:

67984

Other (OTH)

AF:

0.309

AC:

652

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1600

3200

4800

6400

8000

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

504

1008

1512

2016

2520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.278

Hom.:

31952

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

(source)

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

PhyloP100

5.8

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

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over