rs115490148

Positions:

• chr18-59436151-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_133459.4(CCBE1):​c.988-10A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00409 in 1,613,006 control chromosomes in the GnomAD database, including 239 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (135 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (104 hom.)
• Consequence: CCBE1 NM_133459.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001345
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.63

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 18-59436151-T-C is Benign according to our data. Variant chr18-59436151-T-C is described in ClinVar as [Benign]. Clinvar id is 262357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-59436151-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCBE1	NM_133459.4	c.988-10A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000439986.9	NP_597716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCBE1	ENST00000439986.9	c.988-10A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_133459.4	ENSP00000404464	P1

Frequencies

GnomAD3 genomes AF: 0.0219 AC: 3323 AN: 152076 Hom.: 135 Cov.: 32

Gnomad AFR AF: 0.0759

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00812

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00579 AC: 1454 AN: 250958 Hom.: 55 AF XY: 0.00444 AC XY: 603 AN XY: 135712

Gnomad AFR exome AF: 0.0755

Gnomad AMR exome AF: 0.00448

Gnomad ASJ exome AF: 0.000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000274

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00224 AC: 3266 AN: 1460812 Hom.: 104 Cov.: 30 AF XY: 0.00190 AC XY: 1381 AN XY: 726778

Gnomad4 AFR exome AF: 0.0745

Gnomad4 AMR exome AF: 0.00478

Gnomad4 ASJ exome AF: 0.000957

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000142

Gnomad4 OTH exome AF: 0.00555

GnomAD4 genome AF: 0.0219 AC: 3338 AN: 152194 Hom.: 135 Cov.: 32 AF XY: 0.0210 AC XY: 1561 AN XY: 74408

Gnomad4 AFR AF: 0.0761

Gnomad4 AMR AF: 0.00811

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0169 Hom.: 23

Bravo AF: 0.0250

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

Hennekam lymphangiectasia-lymphedema syndrome 1 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.0040
DANN	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000013
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs115490148; hg19: chr18-57103383;