rs121908253

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_133459.4(CCBE1):c.472C>T(p.Arg158Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000213 in 1,613,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

CCBE1
NM_133459.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:4O:1

Conservation

PhyloP100: 2.66

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:

CCBE1 (HGNC:):

CCBE1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 18-59466820-G-A is Pathogenic according to our data. Variant chr18-59466820-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 449.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, not_provided=1, Likely_pathogenic=3}. Variant chr18-59466820-G-A is described in Lovd as [Likely_pathogenic]. Variant chr18-59466820-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.411477). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCBE1	NM_133459.4 linkuse as main transcript	c.472C>T	p.Arg158Cys	missense_variant	5/11	ENST00000439986.9	NP_597716.1	Q6UXH8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCBE1	ENST00000439986.9 linkuse as main transcript	c.472C>T	p.Arg158Cys	missense_variant	5/11	1	NM_133459.4	ENSP00000404464.2		Q6UXH8-1

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.000472

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000207

AC:

AN:

251206

Hom.:

AF XY:

0.000184

AC XY:

AN XY:

135758

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.000300

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000213

AC:

311

AN:

1461168

Hom.:

Cov.:

AF XY:

0.000213

AC XY:

155

AN XY:

726924

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.000278

Gnomad4 FIN exome

AF:

0.000525

Gnomad4 NFE exome

AF:

0.000204

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000217

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.000472

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000178

Hom.:

Bravo

AF:

0.000181

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000222

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Uncertain:1

Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 27, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 158 of the CCBE1 protein (p.Arg158Cys). This variant is present in population databases (rs121908253, gnomAD 0.04%). This missense change has been observed in individual(s) with Hennekam lymphangiectasia-lymphedema syndrome (PMID: 19935664, 32472549, 32629717). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 449). 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 not expected to disrupt CCBE1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect CCBE1 function (PMID: 25814692). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2024	Published functional studies demonstrate activity comparable to wildtype and that the variant does not affect the ability of the protein to activate VEGFC processing (PMID: 19935664, 25814692); 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: 26686525, 25925991, 33507128, 32472549, 19935664, 34426522, 32629717, 25814692) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Hennekam lymphangiectasia-lymphedema syndrome 1

Pathogenic:3Uncertain:1Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2009	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PP3+PM3_Strong+PP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	3billion	Sep 20, 2024	The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.021%).In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.75 (>=0.6, sensitivity 0.68 and specificity 0.92)]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Dec 21, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Hennekam lymphangiectasia-lymphedema syndrome 1, (MIM#235510). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (58 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 24 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated calcium-binding EGF domain (DECIPHER). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. This alternative change, p.(Arg158His), has been reported as a VUS (ClinVar). (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as a VUS, likely pathogenic and pathogenic (ClinVar, LOVD). It has also been observed in two compound heterozygous individuals with Hennekam syndrome or lymphangiectasia and lymphoedema, and a homozygous individual with intestinal lymphangiectasia (PMID: 19935664, PMID: 32472549, PMID: 32629717). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1010 - Functional evidence for this variant is inconclusive. Rescue attempts of zebrafish knockdown demonstrated partial rescue, and this variant did not affect VEGFC signalling both in vitro and in vivo (PMID: 19935664, PMID: 25814692). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 14, 2023

Variant summary: CCBE1 c.472C>T (p.Arg158Cys) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 251206 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CCBE1 causing Hennekam Lymphangiectasia-Lymphedema Syndrome (0.00021 vs 0.00056), allowing no conclusion about variant significance. c.472C>T has been reported in the literature in individuals affected with Hennekam Lymphangiectasia-Lymphedema Syndrome (examples: Alders_2009, Ren_2020 and Fattorusso_2020). These data indicate that the variant may be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function. These results showed conflcting effects on protein function (example: Alders_2009 and Roukens_2015). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic, and as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

CCBE1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 01, 2022

The CCBE1 c.472C>T variant is predicted to result in the amino acid substitution p.Arg158Cys. This variant was reported in the compound heterozygous state along with a premature termination variant in a patient with lymphatic dysplasia (Alders et al 2009. PubMed ID: 19935664). This variant was also reported in the homozygous state in a patient with intestinal lymphangiectasia, edema of the lower extremities and facial dysmorphisms (Fattorusso et al 2020. PubMed ID: 32629717). This variant is reported in 0.036% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-57134052-G-A). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.080

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.74

D;D;T

Eigen

Benign

-0.069

Eigen_PC

Benign

-0.0011

FATHMM_MKL

Uncertain

0.81

LIST_S2

Pathogenic

0.98

.;D;D

M_CAP

Pathogenic

0.42

MetaRNN

Benign

0.41

T;T;T

MetaSVM

Uncertain

0.46

MutationAssessor

Pathogenic

3.8

H;H;.

PrimateAI

Benign

0.24

PROVEAN

Uncertain

-3.3

D;.;.

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0060

D;.;.

Sift4G

Pathogenic

0.0010

D;.;D

Polyphen

0.0080

B;B;.

Vest4

0.90

MVP

0.93

MPC

0.43

ClinPred

0.71

GERP RS

3.3

Varity_R

0.68

gMVP

0.76

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