18-27952209-C-A

Variant names:

• chr18-27952209-C-A
• rs200373316
• NM_001792.5:c.2665G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001792.5(CDH2):​c.2665G>T​(p.Asp889Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D889N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH2 NM_001792.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.17
• Publications: 1 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
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

CDH2-AS1 (HGNC:40138):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH2	NM_001792.5	MANE Select	c.2665G>T	p.Asp889Tyr	missense	Exon 16 of 16	NP_001783.2
	CDH2	NM_001308176.2		c.2572G>T	p.Asp858Tyr	missense	Exon 15 of 15	NP_001295105.1	P19022-2
	CDH2-AS1	NR_199051.1		n.156-2309C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH2	ENST00000269141.8	TSL:1 MANE Select	c.2665G>T	p.Asp889Tyr	missense	Exon 16 of 16	ENSP00000269141.3	P19022-1
	CDH2	ENST00000876838.1		c.2662G>T	p.Asp888Tyr	missense	Exon 16 of 16	ENSP00000546897.1
	CDH2	ENST00000399380.7	TSL:2	c.2572G>T	p.Asp858Tyr	missense	Exon 15 of 15	ENSP00000382312.3	P19022-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		6.2
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.75		Loss of disorder (P = 0.0116)
MVP		0.92
MPC		1.1
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
gMVP		0.89

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: rs200373316; hg19: chr18-25532173;