18-59431120-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_133459.4(CCBE1):c.*4788T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0372 in 152,318 control chromosomes in the GnomAD database, including 187 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.037 (187 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: CCBE1 NM_133459.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0620

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=-0.77).
• BP6: Variant 18-59431120-A-G is Benign according to our data. Variant chr18-59431120-A-G is described in ClinVar as [Benign]. Clinvar id is 327589.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0372 (5669/152318) while in subpopulation NFE AF= 0.0472 (3213/68026). AF 95% confidence interval is 0.0459. There are 187 homozygotes in gnomad4. There are 2966 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 187 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCBE1	NM_133459.4	c.*4788T>C		3_prime_UTR_variant	11/11	ENST00000439986.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCBE1	ENST00000439986.9	c.*4788T>C		3_prime_UTR_variant	11/11	1	NM_133459.4	P1
CCBE1	ENST00000649564.1	c.*4788T>C		3_prime_UTR_variant	12/12			P1
CCBE1	ENST00000650467.2	c.*4788T>C		3_prime_UTR_variant	9/9

Frequencies

GnomAD3 genomes AF: 0.0372 AC: 5668 AN: 152200 Hom.: 187 Cov.: 33

Gnomad AFR AF: 0.00743

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0321

Gnomad ASJ AF: 0.0597

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0472

Gnomad OTH AF: 0.0483

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.0372 AC: 5669 AN: 152318 Hom.: 187 Cov.: 33 AF XY: 0.0398 AC XY: 2966 AN XY: 74486

Gnomad4 AFR AF: 0.00743

Gnomad4 AMR AF: 0.0320

Gnomad4 ASJ AF: 0.0597

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0182

Gnomad4 FIN AF: 0.115

Gnomad4 NFE AF: 0.0472

Gnomad4 OTH AF: 0.0478

Alfa AF: 0.0175 Hom.: 12

Bravo AF: 0.0314

Asia WGS AF: 0.00895 AC: 31 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	-0.77
Cadd	Benign	6.9
Dann	Benign	0.68

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: rs77728352; hg19: chr18-57098352;