rs72958116

Variant names:

• chr18-59435894-G-A
• rs72958116
• ENST00000589116.2:n.943C>T

Your query was ambiguous. Multiple possible variants found:

• chr18-59435894-G-A
• chr18-59435894-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000589116.2(CCBE1):​n.943C>T variant causes a non coding transcript exon 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0095 (14 hom., cov: 32)
  • Exomes 𝑓: 0.012 (147 hom.)
• Consequence: CCBE1 ENST00000589116.2 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.314
• Publications: 2 publications found

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]

CCBE1 Gene-Disease associations (from GenCC):

• Hennekam lymphangiectasia-lymphedema syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Hennekam syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCBE1	NM_133459.4	c.*14C>T		3_prime_UTR_variant	Exon 11 of 11	ENST00000439986.9	NP_597716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCBE1	ENST00000439986.9	c.*14C>T		3_prime_UTR_variant	Exon 11 of 11	1	NM_133459.4	ENSP00000404464.2

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

GnomAD2 exomes AF: 0.0101 AC: 2533 AN: 250470 AF XY: 0.0110

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 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

African (AFR) AF: 0.00192 AC: 64 AN: 33280

American (AMR) AF: 0.00818 AC: 366 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 338 AN: 26078

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39644

South Asian (SAS) AF: 0.0188 AC: 1619 AN: 86028

European-Finnish (FIN) AF: 0.00210 AC: 112 AN: 53416

Middle Eastern (MID) AF: 0.0145 AC: 83 AN: 5740

European-Non Finnish (NFE) AF: 0.0131 AC: 14486 AN: 1102424

Other (OTH) AF: 0.0127 AC: 760 AN: 60044

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

African (AFR) AF: 0.00265 AC: 110 AN: 41542

American (AMR) AF: 0.0156 AC: 238 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00951 AC: 33 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.0177 AC: 85 AN: 4802

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10598

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0132 AC: 899 AN: 68014

Other (OTH) AF: 0.0123 AC: 26 AN: 2110

Alfa AF: 0.0108 Hom.: 5

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

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hennekam lymphangiectasia-lymphedema syndrome 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.31
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

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