18-59431112-C-T

Position:

• chr18-59431112-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_133459.4(CCBE1):​c.*4796G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.817 in 152,192 control chromosomes in the GnomAD database, including 50,948 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.82 (50947 hom., cov: 32)
  • Exomes 𝑓: 1.0 (1 hom.)
• Consequence: CCBE1 NM_133459.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.30

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 18-59431112-C-T is Benign according to our data. Variant chr18-59431112-C-T is described in ClinVar as [Benign]. Clinvar id is 327588.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.873 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCBE1	NM_133459.4	c.*4796G>A		3_prime_UTR_variant	11/11	ENST00000439986.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCBE1	ENST00000439986.9	c.*4796G>A		3_prime_UTR_variant	11/11	1	NM_133459.4	P1
CCBE1	ENST00000649564.1	c.*4796G>A		3_prime_UTR_variant	12/12			P1
CCBE1	ENST00000650467.2	c.*4796G>A		3_prime_UTR_variant	9/9

Frequencies

GnomAD3 genomes AF: 0.818 AC: 124330 AN: 152072 Hom.: 50928 Cov.: 32

Gnomad AFR AF: 0.872

Gnomad AMI AF: 0.818

Gnomad AMR AF: 0.782

Gnomad ASJ AF: 0.813

Gnomad EAS AF: 0.734

Gnomad SAS AF: 0.896

Gnomad FIN AF: 0.760

Gnomad MID AF: 0.848

Gnomad NFE AF: 0.803

Gnomad OTH AF: 0.792

GnomAD4 exome AF: 1.00 AC: 2 AN: 2 Hom.: 1 Cov.: 0 AF XY: 1.00 AC XY: 2 AN XY: 2

Gnomad4 NFE exome AF: 1.00

GnomAD4 genome AF: 0.817 AC: 124396 AN: 152190 Hom.: 50947 Cov.: 32 AF XY: 0.813 AC XY: 60522 AN XY: 74404

Gnomad4 AFR AF: 0.871

Gnomad4 AMR AF: 0.781

Gnomad4 ASJ AF: 0.813

Gnomad4 EAS AF: 0.734

Gnomad4 SAS AF: 0.896

Gnomad4 FIN AF: 0.760

Gnomad4 NFE AF: 0.803

Gnomad4 OTH AF: 0.787

Alfa AF: 0.815 Hom.: 23003

Bravo AF: 0.816

Asia WGS AF: 0.805 AC: 2801 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	-0.89
CADD	Benign	0.31
DANN	Benign	0.51

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: rs1048008; hg19: chr18-57098344;