rs1129748

Variant names:

• chr18-59430963-G-T
• rs1129748
• NM_133459.4:c.*4945C>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_133459.4(CCBE1):​c.*4945C>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 0.789 in 152,220 control chromosomes in the GnomAD database, including 47,406 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.79 (47406 hom., cov: 34)
  • Failed GnomAD Quality Control
• Consequence: CCBE1 NM_133459.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.64
• 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• Hennekam syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 18-59430963-G-T is Benign according to our data. Variant chr18-59430963-G-T is described in ClinVar as Benign. ClinVar VariationId is 327583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.873 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133459.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCBE1	NM_133459.4	MANE Select	c.*4945C>A		3_prime_UTR	Exon 11 of 11	NP_597716.1	Q6UXH8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCBE1	ENST00000439986.9	TSL:1 MANE Select	c.*4945C>A		3_prime_UTR	Exon 11 of 11	ENSP00000404464.2	Q6UXH8-1
	CCBE1	ENST00000649564.1		c.*4945C>A		3_prime_UTR	Exon 12 of 12	ENSP00000497183.1	Q6UXH8-1
	CCBE1	ENST00000650467.2		c.*4945C>A		3_prime_UTR	Exon 9 of 9	ENSP00000496897.2	A0A3B3IRL6

Frequencies

GnomAD3 genomes AF: 0.789 AC: 120050 AN: 152102 Hom.: 47392 Cov.: 34

Gnomad AFR AF: 0.797

Gnomad AMI AF: 0.815

Gnomad AMR AF: 0.768

Gnomad ASJ AF: 0.811

Gnomad EAS AF: 0.731

Gnomad SAS AF: 0.896

Gnomad FIN AF: 0.754

Gnomad MID AF: 0.842

Gnomad NFE AF: 0.790

Gnomad OTH AF: 0.773

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.789 AC: 120106 AN: 152220 Hom.: 47406 Cov.: 34 AF XY: 0.787 AC XY: 58539 AN XY: 74404

African (AFR) AF: 0.797 AC: 33118 AN: 41550

American (AMR) AF: 0.767 AC: 11733 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.811 AC: 2817 AN: 3472

East Asian (EAS) AF: 0.731 AC: 3784 AN: 5174

South Asian (SAS) AF: 0.895 AC: 4316 AN: 4822

European-Finnish (FIN) AF: 0.754 AC: 7982 AN: 10582

Middle Eastern (MID) AF: 0.840 AC: 247 AN: 294

European-Non Finnish (NFE) AF: 0.790 AC: 53746 AN: 68010

Other (OTH) AF: 0.768 AC: 1620 AN: 2110

Alfa AF: 0.794 Hom.: 11114

Bravo AF: 0.785

Asia WGS AF: 0.798 AC: 2776 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hennekam lymphangiectasia-lymphedema syndrome 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	15
DANN	Benign	0.68
PhyloP100		2.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs1129748; hg19: chr18-57098195;