NM_133459.4:c.775+12A>G

Variant names:

• chr18-59447971-T-C
• rs1893788
• NM_133459.4:c.775+12A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_133459.4(CCBE1):​c.775+12A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.556 in 1,613,712 control chromosomes in the GnomAD database, including 252,127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (27096 hom., cov: 32)
  • Exomes 𝑓: 0.55 (225031 hom.)
• Consequence: CCBE1 NM_133459.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.719
• Publications: 8 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 18-59447971-T-C is Benign according to our data. Variant chr18-59447971-T-C is described in ClinVar as Benign. ClinVar VariationId is 262355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.71 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCBE1	NM_133459.4	c.775+12A>G		intron_variant	Intron 7 of 10	ENST00000439986.9	NP_597716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCBE1	ENST00000439986.9	c.775+12A>G		intron_variant	Intron 7 of 10	1	NM_133459.4	ENSP00000404464.2

Frequencies

GnomAD3 genomes AF: 0.590 AC: 89598 AN: 151988 Hom.: 27051 Cov.: 32

Gnomad AFR AF: 0.717

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.555

Gnomad ASJ AF: 0.612

Gnomad EAS AF: 0.336

Gnomad SAS AF: 0.479

Gnomad FIN AF: 0.484

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.565

Gnomad OTH AF: 0.579

GnomAD2 exomes AF: 0.527 AC: 132204 AN: 251048 AF XY: 0.524

Gnomad AFR exome AF: 0.717

Gnomad AMR exome AF: 0.491

Gnomad ASJ exome AF: 0.606

Gnomad EAS exome AF: 0.331

Gnomad FIN exome AF: 0.485

Gnomad NFE exome AF: 0.557

Gnomad OTH exome AF: 0.547

GnomAD4 exome AF: 0.552 AC: 806905 AN: 1461606 Hom.: 225031 Cov.: 63 AF XY: 0.550 AC XY: 399590 AN XY: 727096

African (AFR) AF: 0.725 AC: 24285 AN: 33474

American (AMR) AF: 0.505 AC: 22581 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.607 AC: 15867 AN: 26130

East Asian (EAS) AF: 0.348 AC: 13795 AN: 39694

South Asian (SAS) AF: 0.475 AC: 40926 AN: 86250

European-Finnish (FIN) AF: 0.488 AC: 26012 AN: 53340

Middle Eastern (MID) AF: 0.640 AC: 3671 AN: 5734

European-Non Finnish (NFE) AF: 0.563 AC: 626323 AN: 1111886

Other (OTH) AF: 0.554 AC: 33445 AN: 60384

GnomAD4 genome AF: 0.590 AC: 89700 AN: 152106 Hom.: 27096 Cov.: 32 AF XY: 0.582 AC XY: 43281 AN XY: 74364

African (AFR) AF: 0.717 AC: 29765 AN: 41510

American (AMR) AF: 0.556 AC: 8487 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.612 AC: 2124 AN: 3468

East Asian (EAS) AF: 0.337 AC: 1736 AN: 5158

South Asian (SAS) AF: 0.480 AC: 2311 AN: 4818

European-Finnish (FIN) AF: 0.484 AC: 5126 AN: 10580

Middle Eastern (MID) AF: 0.653 AC: 192 AN: 294

European-Non Finnish (NFE) AF: 0.565 AC: 38382 AN: 67978

Other (OTH) AF: 0.579 AC: 1223 AN: 2112

Alfa AF: 0.584 Hom.: 5535

Bravo AF: 0.600

Asia WGS AF: 0.449 AC: 1562 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 53% of total chromosomes in ExAC

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 77% of patients studied by a panel of primary immunodeficiencies. Number of patients: 73. Only high quality variants are reported.

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hennekam lymphangiectasia-lymphedema syndrome 1 Benign:3

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.8
DANN	Benign	0.36
PhyloP100		-0.72
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1893788; hg19: chr18-57115203; COSMIC: COSV67950151; COSMIC: COSV67950151;