rs72958116

Positions:

• chr18-59435894-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000439986.9(CCBE1):​c.*14C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,603,590 control chromosomes in the GnomAD database, including 161 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0095 (14 hom., cov: 32)
  • Exomes 𝑓: 0.012 (147 hom.)
• Consequence: CCBE1 ENST00000439986.9 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.314

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=-0.82).
• BP6: Variant 18-59435894-G-A is Benign according to our data. Variant chr18-59435894-G-A is described in ClinVar as [Benign]. Clinvar id is 262349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-59435894-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00945 (1439/152214) while in subpopulation SAS AF= 0.0177 (85/4802). AF 95% confidence interval is 0.0147. There are 14 homozygotes in gnomad4. There are 675 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCBE1	NM_133459.4	c.*14C>T		3_prime_UTR_variant	11/11	ENST00000439986.9	NP_597716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCBE1	ENST00000439986.9	c.*14C>T		3_prime_UTR_variant	11/11	1	NM_133459.4	ENSP00000404464	P1

Frequencies

GnomAD3 genomes AF: 0.00944 AC: 1436 AN: 152096 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00266

Gnomad AMI AF: 0.0275

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.00951

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0171

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.0101 AC: 2533 AN: 250470 Hom.: 28 AF XY: 0.0110 AC XY: 1484 AN XY: 135450

Gnomad AFR exome AF: 0.00141

Gnomad AMR exome AF: 0.00778

Gnomad ASJ exome AF: 0.0135

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0191

Gnomad FIN exome AF: 0.00245

Gnomad NFE exome AF: 0.0125

Gnomad OTH exome AF: 0.00929

GnomAD4 exome AF: 0.0123 AC: 17829 AN: 1451376 Hom.: 147 Cov.: 27 AF XY: 0.0125 AC XY: 9025 AN XY: 722838

Gnomad4 AFR exome AF: 0.00192

Gnomad4 AMR exome AF: 0.00818

Gnomad4 ASJ exome AF: 0.0130

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0188

Gnomad4 FIN exome AF: 0.00210

Gnomad4 NFE exome AF: 0.0131

Gnomad4 OTH exome AF: 0.0127

GnomAD4 genome AF: 0.00945 AC: 1439 AN: 152214 Hom.: 14 Cov.: 32 AF XY: 0.00907 AC XY: 675 AN XY: 74434

Gnomad4 AFR AF: 0.00265

Gnomad4 AMR AF: 0.0156

Gnomad4 ASJ AF: 0.00951

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0177

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.0132

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0120 Hom.: 3

Bravo AF: 0.00935

Asia WGS AF: 0.00722 AC: 26 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

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

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Hennekam lymphangiectasia-lymphedema syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.1
DANN	Benign	0.52

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

Other links and lift over

dbSNP: rs72958116; hg19: chr18-57103126; COSMIC: COSV67949203;