rs1148374

Variant names:

• chr18-28070318-T-A
• rs1148374
• NM_001792.5:c.173-56409A>T

Variant summary

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

The NM_001792.5(CDH2):​c.173-56409A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.307 in 152,132 control chromosomes in the GnomAD database, including 8,638 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 0.31 (8638 hom., cov: 32)
• Consequence: CDH2 NM_001792.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.804
• Publications: 5 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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.423 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH2	NM_001792.5	c.173-56409A>T		intron_variant	Intron 2 of 15	ENST00000269141.8	NP_001783.2
CDH2	XM_017025514.3	c.173-56409A>T		intron_variant	Intron 2 of 15		XP_016881003.1
CDH2	XM_011525788.1	c.-83-56409A>T		intron_variant	Intron 2 of 15		XP_011524090.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH2	ENST00000269141.8	c.173-56409A>T		intron_variant	Intron 2 of 15	1	NM_001792.5	ENSP00000269141.3

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46745 AN: 152014 Hom.: 8635 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.378

Gnomad EAS AF: 0.184

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.417

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.427

Gnomad OTH AF: 0.340

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

GnomAD4 genome AF: 0.307 AC: 46755 AN: 152132 Hom.: 8638 Cov.: 32 AF XY: 0.304 AC XY: 22628 AN XY: 74374

African (AFR) AF: 0.106 AC: 4415 AN: 41540

American (AMR) AF: 0.272 AC: 4153 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.378 AC: 1308 AN: 3464

East Asian (EAS) AF: 0.184 AC: 949 AN: 5168

South Asian (SAS) AF: 0.266 AC: 1278 AN: 4812

European-Finnish (FIN) AF: 0.417 AC: 4409 AN: 10578

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.427 AC: 29026 AN: 67970

Other (OTH) AF: 0.344 AC: 726 AN: 2112

Alfa AF: 0.365 Hom.: 1400

Bravo AF: 0.287

Asia WGS AF: 0.240 AC: 835 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.23
DANN	Benign	0.43
PhyloP100		-0.80
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: rs1148374; hg19: chr18-25650282;