rs121908250

Positions:

chr18-59480228-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_133459.4(CCBE1):c.223T>A(p.Cys75Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00017 in 1,596,906 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

CCBE1
NM_133459.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 6.05

Variant links:

Genes affected

CCBE1 (HGNC:29426): (collagen and calcium binding EGF domains 1) This gene is thought to function in extracellular matrix remodeling and migration. It is predominantly expressed in the ovary, but down regulated in ovarian cancer cell lines and primary carcinomas, suggesting its role as a tumour suppressor. Mutations in this gene have been associated with Hennekam lymphangiectasia-lymphedema syndrome, a generalized lymphatic dysplasia in humans. [provided by RefSeq, Mar 2010]

CCBE1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.796

PP5

Variant 18-59480228-A-T is Pathogenic according to our data. Variant chr18-59480228-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-59480228-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCBE1	NM_133459.4 linkuse as main transcript	c.223T>A	p.Cys75Ser	missense_variant	3/11	ENST00000439986.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCBE1	ENST00000439986.9 linkuse as main transcript	c.223T>A	p.Cys75Ser	missense_variant	3/11	1	NM_133459.4	P1	Q6UXH8-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000360

AC:

AN:

250120

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

135346

show subpopulations

Gnomad AFR exome

AF:

0.000187

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000531

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000181

AC:

262

AN:

1444680

Hom.:

Cov.:

AF XY:

0.000174

AC XY:

125

AN XY:

719936

show subpopulations

Gnomad4 AFR exome

AF:

0.0000906

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:

0.000230

Gnomad4 OTH exome

AF:

0.000117

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000141

Hom.:

Bravo

AF:

0.0000793

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000548

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 20, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 2022	Published functional studies demonstrate a damaging effect with reduced ability to rescue zebrafish ccbe1 knockdown morphants (Alders et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24167460, 19935664, 19911200, 34234628) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 75 of the CCBE1 protein (p.Cys75Ser). This variant is present in population databases (rs121908250, gnomAD 0.02%). This missense change has been observed in individuals with clinical features of Hennekam lymphangiectasia-lymphedema syndrome (PMID: 19911200, 19935664, 22239599, 23653581, 24167460). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 445). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CCBE1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CCBE1 function (PMID: 19935664). For these reasons, this variant has been classified as Pathogenic. -

Hennekam lymphangiectasia-lymphedema syndrome 1

Pathogenic:1Other:1

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2010	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.32

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.075

T;T;T

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.86

.;D;T

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.80

D;D;D

MetaSVM

Uncertain

0.56

MutationAssessor

Benign

1.8

L;L;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-3.8

D;.;.

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0040

D;.;.

Sift4G

Uncertain

0.0020

D;.;D

Polyphen

0.98

D;D;.

Vest4

0.95

MutPred

0.83

Loss of methylation at K76 (P = 0.0483);Loss of methylation at K76 (P = 0.0483);.;

MVP

0.96

MPC

0.14

ClinPred

0.22

GERP RS

5.6

Varity_R

0.56

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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