18-59697220-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_133459.4(CCBE1):c.123C>A(p.Asp41Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00326 in 1,548,800 control chromosomes in the GnomAD database, including 158 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D41N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.017 ( 83 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 75 hom. )

Consequence

CCBE1
NM_133459.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.85

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

Hennekam lymphangiectasia-lymphedema syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Hennekam syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CCBE1 links:

ENSG00000267774 (HGNC:):

ENSG00000267774 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020519793).

BP6

Variant 18-59697220-G-T is Benign according to our data. Variant chr18-59697220-G-T is described in ClinVar as Benign. ClinVar VariationId is 327710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0579 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCBE1	NM_133459.4 link	c.123C>A	p.Asp41Glu	missense_variant	Exon 1 of 11	ENST00000439986.9	NP_597716.1	Q6UXH8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCBE1	ENST00000439986.9 link	c.123C>A	p.Asp41Glu	missense_variant	Exon 1 of 11	1	NM_133459.4	ENSP00000404464.2		Q6UXH8-1

Frequencies

GnomAD3 genomes

AF:

0.0171

AC:

2602

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0599

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00576

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:

0.000132

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.00393

AC:

580

AN:

147706

AF XY:

0.00308

show subpopulations

Gnomad AFR exome

AF:

0.0621

Gnomad AMR exome

AF:

0.00260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000130

Gnomad OTH exome

AF:

0.00280

GnomAD4 exome

AF:

0.00175

AC:

2440

AN:

1396486

Hom.:

Cov.:

AF XY:

0.00151

AC XY:

1043

AN XY:

688742

show subpopulations

African (AFR)

AF:

0.0649

AC:

2045

AN:

31532

American (AMR)

AF:

0.00303

AC:

108

AN:

35692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25152

East Asian (EAS)

AF:

0.00

AC:

AN:

35724

South Asian (SAS)

AF:

0.000101

AC:

AN:

79172

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47922

Middle Eastern (MID)

AF:

0.00188

AC:

AN:

4776

European-Non Finnish (NFE)

AF:

0.0000297

AC:

AN:

1078678

Other (OTH)

AF:

0.00411

AC:

238

AN:

57838

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

128

256

384

512

640

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0171

AC:

2609

AN:

152314

Hom.:

Cov.:

AF XY:

0.0164

AC XY:

1219

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0599

AC:

2489

AN:

41564

American (AMR)

AF:

0.00575

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68034

Other (OTH)

AF:

0.0109

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

127

254

381

508

635

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00390

Hom.:

Bravo

AF:

0.0197

ESP6500AA

AF:

0.0515

AC:

192

ESP6500EA

AF:

0.000282

AC:

ExAC

AF:

0.00362

AC:

171

Asia WGS

AF:

0.00404

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 22, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hennekam lymphangiectasia-lymphedema syndrome 1

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.037

T;T

Eigen

Benign

0.060

Eigen_PC

Benign

0.033

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.56

.;T

MetaRNN

Benign

0.0021

T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

1.2

L;L

PhyloP100

3.9

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.2

N;.

REVEL

Uncertain

0.32

Sift

Benign

0.045

D;.

Sift4G

Uncertain

0.016

D;.

Polyphen

0.98

D;D

Vest4

0.072

MutPred

0.21

Gain of glycosylation at P39 (P = 0.0743);Gain of glycosylation at P39 (P = 0.0743);

MVP

0.91

MPC

0.38

ClinPred

0.022

GERP RS

4.1

PromoterAI

-0.056

Neutral

(source)

Varity_R

0.14

gMVP

0.27

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over