18-59431062-C-T

Position:

• chr18-59431062-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6_Moderate BS1

The NM_133459.4(CCBE1):​c.*4846G>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 0.00178 in 152,304 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CCBE1 NM_133459.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.217

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 -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 18-59431062-C-T is Benign according to our data. Variant chr18-59431062-C-T is described in ClinVar as [Benign]. Clinvar id is 327585.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00178 (271/152304) while in subpopulation EAS AF= 0.0371 (192/5182). AF 95% confidence interval is 0.0328. There are 1 homozygotes in gnomad4. There are 145 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCBE1	NM_133459.4	c.*4846G>A		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	c.*4846G>A		3_prime_UTR_variant	11/11	1	NM_133459.4	ENSP00000404464.2
CCBE1	ENST00000649564	c.*4846G>A		3_prime_UTR_variant	12/12			ENSP00000497183.1
CCBE1	ENST00000650467.2	c.*4846G>A		3_prime_UTR_variant	9/9			ENSP00000496897.2

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 272 AN: 152186 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.0370

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00478

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

Gnomad4 FIN exome AF: 0.00

GnomAD4 genome AF: 0.00178 AC: 271 AN: 152304 Hom.: 1 Cov.: 34 AF XY: 0.00195 AC XY: 145 AN XY: 74464

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.0371

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.000886 Hom.: 0

Bravo AF: 0.00209

Asia WGS AF: 0.0150 AC: 51 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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	2.4
DANN	Benign	0.64

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: rs141622451; hg19: chr18-57098294;