rs116675104

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_133459.4(CCBE1):c.499C>T(p.Arg167Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,613,702 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts 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. R167Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 25 hom. )

Consequence

CCBE1
NM_133459.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 7.30

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0058504045).

BP6

Variant 18-59466793-G-A is Benign according to our data. Variant chr18-59466793-G-A is described in ClinVar as [Benign]. Clinvar id is 262354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00109 (166/152206) while in subpopulation SAS AF= 0.0149 (72/4826). AF 95% confidence interval is 0.0121. There are 0 homozygotes in gnomad4. There are 87 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCBE1	NM_133459.4 linkuse as main transcript	c.499C>T	p.Arg167Trp	missense_variant	5/11	ENST00000439986.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCBE1	ENST00000439986.9 linkuse as main transcript	c.499C>T	p.Arg167Trp	missense_variant	5/11	1	NM_133459.4	P1	Q6UXH8-1

Frequencies

GnomAD3 genomes

AF:

0.00109

AC:

166

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0149

Gnomad FIN

AF:

0.0000946

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000559

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.00248

AC:

623

AN:

251232

Hom.:

AF XY:

0.00332

AC XY:

451

AN XY:

135782

show subpopulations

Gnomad AFR exome

AF:

0.000861

Gnomad AMR exome

AF:

0.000665

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.0167

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000449

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00132

AC:

1925

AN:

1461496

Hom.:

Cov.:

AF XY:

0.00183

AC XY:

1330

AN XY:

727042

show subpopulations

Gnomad4 AFR exome

AF:

0.000777

Gnomad4 AMR exome

AF:

0.000693

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0162

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000267

Gnomad4 OTH exome

AF:

0.00184

GnomAD4 genome

AF:

0.00109

AC:

166

AN:

152206

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.00108

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0149

Gnomad4 FIN

AF:

0.0000946

Gnomad4 NFE

AF:

0.000559

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.000590

Hom.:

Bravo

AF:

0.000680

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00282

AC:

342

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.000872

EpiControl

AF:

0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Hennekam lymphangiectasia-lymphedema syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.15

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.36

T;T;T

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.98

MetaRNN

Benign

0.0059

T;T;T

MetaSVM

Uncertain

0.67

MutationAssessor

Benign

1.3

L;L;.

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.20

N;.;.

REVEL

Uncertain

0.49

Sift

Uncertain

0.0040

D;.;.

Sift4G

Uncertain

0.017

D;.;D

Polyphen

0.99

D;D;.

Vest4

0.38

MVP

0.97

MPC

0.28

ClinPred

0.043

GERP RS

5.2

Varity_R

0.14

gMVP

0.61

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