18-27952210-G-T

Position:

chr18-27952210-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The ENST00000269141.8(CDH2):c.2664C>A(p.Asn888Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. N888N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CDH2
ENST00000269141.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.599

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 links:

(HGNC:):

links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CDH2	NM_001792.5 linkuse as main transcript	c.2664C>A	p.Asn888Lys	missense_variant	16/16	ENST00000269141.8	NP_001783.2
CDH2	NM_001308176.2 linkuse as main transcript	c.2571C>A	p.Asn857Lys	missense_variant	15/15		NP_001295105.1
CDH2	XM_011525788.1 linkuse as main transcript	c.2409C>A	p.Asn803Lys	missense_variant	16/16		XP_011524090.1
CDH2	XM_017025514.3 linkuse as main transcript	c.2514+11147C>A		intron_variant			XP_016881003.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH2	ENST00000269141.8 linkuse as main transcript	c.2664C>A	p.Asn888Lys	missense_variant	16/16	1	NM_001792.5	ENSP00000269141	P1	P19022-1
	ENST00000423367.2 linkuse as main transcript	n.199-2308G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152018

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461486

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727054

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152018

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74246

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	CDH2: PM2, PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 07, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals affected with CDH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 888 of the CDH2 protein (p.Asn888Lys). -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2023

The p.N888K variant (also known as c.2664C>A), located in coding exon 16 of the CDH2 gene, results from a C to A substitution at nucleotide position 2664. The asparagine at codon 888 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Uncertain

0.033

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

T;.

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.096

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.84

T;T

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.83

D;D

MetaSVM

Uncertain

-0.048

MutationAssessor

Uncertain

2.3

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-4.6

D;D

REVEL

Uncertain

0.60

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.010

D;D

Polyphen

0.95

P;.

Vest4

0.58

MutPred

0.70

Gain of methylation at N888 (P = 0.0178);.;

MVP

0.85

MPC

0.92

ClinPred

1.0

GERP RS

-1.4

Varity_R

0.76

gMVP

0.85

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over