Genetic Variant CDH2:c.1599-428T>C (chr18-27989094-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001792.5(CDH2):c.1599-428T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0691 in 152,266 control chromosomes in the GnomAD database, including 400 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.

Frequency

Genomes: 𝑓 0.069 ( 400 hom., cov: 32)

Consequence

CDH2
NM_001792.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0820

Publications

6 publications found

Variant links:

Genes affected

CDH2 (HGNC:1759): (cadherin 2) This gene encodes a classical cadherin and member of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein is proteolytically processed to generate a calcium-dependent cell adhesion molecule and glycoprotein. This protein plays a role in the establishment of left-right asymmetry, development of the nervous system and the formation of cartilage and bone. [provided by RefSeq, Nov 2015]

CDH2 Gene-Disease associations (from GenCC):

agenesis of corpus callosum, cardiac, ocular, and genital syndrome
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
arrhythmogenic right ventricular dysplasia, familial, 14
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
congenital heart disease
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

CDH2 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 (BayesDel_noAF=-0.83).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0837 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CDH2	NM_001792.5 link	c.1599-428T>C	intron_variant	Intron 10 of 15	ENST00000269141.8	NP_001783.2	P19022-1A0A024RC42
CDH2	NM_001308176.2 link	c.1506-428T>C	intron_variant	Intron 9 of 14		NP_001295105.1	P19022-2
CDH2	XM_017025514.3 link	c.1599-428T>C	intron_variant	Intron 10 of 15		XP_016881003.1
CDH2	XM_011525788.1 link	c.1344-428T>C	intron_variant	Intron 10 of 15		XP_011524090.1	C9J126

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH2	ENST00000269141.8 link	c.1599-428T>C		intron_variant	Intron 10 of 15	1	NM_001792.5	ENSP00000269141.3		P19022-1

Frequencies

GnomAD3 genomes

AF:

0.0692

AC:

10532

AN:

152146

Hom.:

400

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0424

Gnomad AMI

AF:

0.113

Gnomad AMR

AF:

0.0387

Gnomad ASJ

AF:

0.0931

Gnomad EAS

AF:

0.0501

Gnomad SAS

AF:

0.0919

Gnomad FIN

AF:

0.106

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0852

Gnomad OTH

AF:

0.0584

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0691

AC:

10523

AN:

152266

Hom.:

400

Cov.:

AF XY:

0.0694

AC XY:

5169

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0423

AC:

1757

AN:

41564

American (AMR)

AF:

0.0386

AC:

591

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0931

AC:

323

AN:

3470

East Asian (EAS)

AF:

0.0502

AC:

260

AN:

5180

South Asian (SAS)

AF:

0.0908

AC:

438

AN:

4826

European-Finnish (FIN)

AF:

0.106

AC:

1122

AN:

10602

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0853

AC:

5798

AN:

68010

Other (OTH)

AF:

0.0573

AC:

121

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

498

995

1493

1990

2488

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

248

372

496

620

<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:

0.0812

Hom.:

1754

Bravo

AF:

0.0636

Asia WGS

AF:

0.0500

AC:

173

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.75

(source)

DANN

Benign

0.68

PhyloP100

-0.082

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over