18-59480160-G-T

Variant names:

• chr18-59480160-G-T
• rs1663549
• NM_133459.4:c.265+26C>A

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.265+26C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.27 in 1,413,438 control chromosomes in the GnomAD database, including 53,500 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6018 hom., cov: 33)
  • Exomes 𝑓: 0.27 (47482 hom.)
• Consequence: CCBE1 NM_133459.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0620
• Publications: 6 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=-0.85).
• BP6: Variant 18-59480160-G-T is Benign according to our data. Variant chr18-59480160-G-T is described in ClinVar as Benign. ClinVar VariationId is 262350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCBE1	NM_133459.4	c.265+26C>A		intron_variant	Intron 3 of 10	ENST00000439986.9	NP_597716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCBE1	ENST00000439986.9	c.265+26C>A		intron_variant	Intron 3 of 10	1	NM_133459.4	ENSP00000404464.2

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42627 AN: 151966 Hom.: 6017 Cov.: 33

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.323

Gnomad AMR AF: 0.269

Gnomad ASJ AF: 0.232

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.279

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.289

Gnomad OTH AF: 0.283

GnomAD2 exomes AF: 0.266 AC: 65452 AN: 246022 AF XY: 0.262

Gnomad AFR exome AF: 0.290

Gnomad AMR exome AF: 0.268

Gnomad ASJ exome AF: 0.237

Gnomad EAS exome AF: 0.220

Gnomad FIN exome AF: 0.281

Gnomad NFE exome AF: 0.285

Gnomad OTH exome AF: 0.275

GnomAD4 exome AF: 0.268 AC: 338373 AN: 1261354 Hom.: 47482 Cov.: 18 AF XY: 0.267 AC XY: 170639 AN XY: 638258

African (AFR) AF: 0.271 AC: 7968 AN: 29418

American (AMR) AF: 0.272 AC: 12017 AN: 44224

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 5928 AN: 24890

East Asian (EAS) AF: 0.183 AC: 7025 AN: 38472

South Asian (SAS) AF: 0.207 AC: 16951 AN: 81772

European-Finnish (FIN) AF: 0.287 AC: 15182 AN: 52978

Middle Eastern (MID) AF: 0.217 AC: 1148 AN: 5288

European-Non Finnish (NFE) AF: 0.277 AC: 258033 AN: 930796

Other (OTH) AF: 0.264 AC: 14121 AN: 53516

GnomAD4 genome AF: 0.280 AC: 42652 AN: 152084 Hom.: 6018 Cov.: 33 AF XY: 0.276 AC XY: 20552 AN XY: 74356

African (AFR) AF: 0.293 AC: 12153 AN: 41494

American (AMR) AF: 0.269 AC: 4111 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 807 AN: 3472

East Asian (EAS) AF: 0.215 AC: 1114 AN: 5186

South Asian (SAS) AF: 0.200 AC: 968 AN: 4830

European-Finnish (FIN) AF: 0.279 AC: 2942 AN: 10556

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.289 AC: 19619 AN: 67964

Other (OTH) AF: 0.279 AC: 588 AN: 2110

Alfa AF: 0.281 Hom.: 1166

Bravo AF: 0.283

Asia WGS AF: 0.214 AC: 744 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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 51% of patients studied by a panel of primary immunodeficiencies. Number of patients: 48. Only high quality variants are reported.

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.1
DANN	Benign	0.41
PhyloP100		-0.062
PromoterAI		-0.0026	Neutral
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: rs1663549; hg19: chr18-57147392;