rs1555630396

Positions:

• chr18-27985134-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM2 PP5_Moderate BP4

The NM_001792.5(CDH2):​c.2075A>G​(p.Asn692Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CDH2 NM_001792.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.55

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a domain Cadherin 5 (size 110) in uniprot entity CADH2_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_001792.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-27985134-T-C is Pathogenic according to our data. Variant chr18-27985134-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 545108.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr18-27985134-T-C is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.19124576). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH2	NM_001792.5	c.2075A>G	p.Asn692Ser	missense_variant	13/16	ENST00000269141.8
CDH2	NM_001308176.2	c.1982A>G	p.Asn661Ser	missense_variant	12/15
CDH2	XM_017025514.3	c.2075A>G	p.Asn692Ser	missense_variant	13/16
CDH2	XM_011525788.1	c.1820A>G	p.Asn607Ser	missense_variant	13/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH2	ENST00000269141.8	c.2075A>G	p.Asn692Ser	missense_variant	13/16	1	NM_001792.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461532 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727112

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cerebral arteriovenous malformation Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital

Feb 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;.
Eigen	Benign	-0.086
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.52	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Benign	0.11
Sift	Benign	0.056	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.017	B;.
Vest4		0.098
MutPred		0.57		Gain of disorder (P = 0.0796);.;
MVP		0.47
MPC		0.24
ClinPred		0.55	D
GERP RS		6.1
Varity_R		0.16
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555630396; hg19: chr18-25565098;