rs61745250

chr18-59439755-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_133459.4(CCBE1):c.837C>T(p.Pro279=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0159 in 1,614,160 control chromosomes in the GnomAD database, including 252 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (17 hom., cov: 33)
  • Exomes 𝑓: 0.016 (235 hom.)
• Consequence: CCBE1 NM_133459.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.36

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 18-59439755-G-A is Benign according to our data. Variant chr18-59439755-G-A is described in ClinVar as [Benign]. Clinvar id is 262356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-59439755-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.36 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0115 (1751/152328) while in subpopulation NFE AF= 0.0191 (1297/68026). AF 95% confidence interval is 0.0182. There are 17 homozygotes in gnomad4. There are 824 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCBE1	NM_133459.4	c.837C>T	p.Pro279=	synonymous_variant	8/11	ENST00000439986.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCBE1	ENST00000439986.9	c.837C>T	p.Pro279=	synonymous_variant	8/11	1	NM_133459.4	P1

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1753 AN: 152210 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.00340

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00883

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0111

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0191

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.0121 AC: 3026 AN: 250740 Hom.: 35 AF XY: 0.0120 AC XY: 1635 AN XY: 135762

Gnomad AFR exome AF: 0.00268

Gnomad AMR exome AF: 0.00587

Gnomad ASJ exome AF: 0.00766

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00255

Gnomad FIN exome AF: 0.0115

Gnomad NFE exome AF: 0.0204

Gnomad OTH exome AF: 0.0110

GnomAD4 exome AF: 0.0163 AC: 23898 AN: 1461832 Hom.: 235 Cov.: 32 AF XY: 0.0158 AC XY: 11526 AN XY: 727216

Gnomad4 AFR exome AF: 0.00182

Gnomad4 AMR exome AF: 0.00566

Gnomad4 ASJ exome AF: 0.00750

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00297

Gnomad4 FIN exome AF: 0.0118

Gnomad4 NFE exome AF: 0.0195

Gnomad4 OTH exome AF: 0.0128

GnomAD4 genome AF: 0.0115 AC: 1751 AN: 152328 Hom.: 17 Cov.: 33 AF XY: 0.0111 AC XY: 824 AN XY: 74496

Gnomad4 AFR AF: 0.00339

Gnomad4 AMR AF: 0.00875

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.0111

Gnomad4 NFE AF: 0.0191

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.0154 Hom.: 7

Bravo AF: 0.0100

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0167

EpiControl AF: 0.0168

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hennekam lymphangiectasia-lymphedema syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
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. -

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

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	0.96
Dann	Benign	0.55

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: rs61745250; hg19: chr18-57106987;