18-28120827-T-C

Variant names:

• chr18-28120827-T-C
• rs11564386
• NM_001792.5:c.172+26846A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001792.5(CDH2):​c.172+26846A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0452 in 152,176 control chromosomes in the GnomAD database, including 184 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 0.045 (184 hom., cov: 32)
• Consequence: CDH2 NM_001792.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.436
• Publications: 4 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0756 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001792.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH2	NM_001792.5	MANE Select	c.172+26846A>G		intron	N/A	NP_001783.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH2	ENST00000269141.8	TSL:1 MANE Select	c.172+26846A>G		intron	N/A	ENSP00000269141.3
	CDH2	ENST00000430882.6	TSL:4	c.-275-23573A>G		intron	N/A	ENSP00000412120.2
	CDH2	ENST00000676445.1		c.-84+26846A>G		intron	N/A	ENSP00000502206.1

Frequencies

GnomAD3 genomes AF: 0.0453 AC: 6881 AN: 152056 Hom.: 184 Cov.: 32

Gnomad AFR AF: 0.0569

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.0266

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.0431

Gnomad SAS AF: 0.0836

Gnomad FIN AF: 0.0456

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0396

Gnomad OTH AF: 0.0416

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

GnomAD4 genome AF: 0.0452 AC: 6881 AN: 152176 Hom.: 184 Cov.: 32 AF XY: 0.0452 AC XY: 3364 AN XY: 74438

African (AFR) AF: 0.0570 AC: 2367 AN: 41542

American (AMR) AF: 0.0265 AC: 405 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0317 AC: 110 AN: 3468

East Asian (EAS) AF: 0.0431 AC: 223 AN: 5170

South Asian (SAS) AF: 0.0822 AC: 397 AN: 4828

European-Finnish (FIN) AF: 0.0456 AC: 483 AN: 10596

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0396 AC: 2695 AN: 67984

Other (OTH) AF: 0.0407 AC: 86 AN: 2112

Alfa AF: 0.0409 Hom.: 227

Bravo AF: 0.0422

Asia WGS AF: 0.0520 AC: 182 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.32
DANN	Benign	0.48
PhyloP100		-0.44
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11564386; hg19: chr18-25700791;