18-59471725-T-C

Variant names:

• chr18-59471725-T-C
• rs12961264
• NM_133459.4:c.266-2118A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_133459.4(CCBE1):​c.266-2118A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 152,134 control chromosomes in the GnomAD database, including 5,604 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 0.26 (5604 hom., cov: 33)
• Consequence: CCBE1 NM_133459.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.169
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.366 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCBE1	NM_133459.4	MANE Select	c.266-2118A>G		intron	N/A	NP_597716.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCBE1	ENST00000439986.9	TSL:1 MANE Select	c.266-2118A>G		intron	N/A	ENSP00000404464.2
	CCBE1	ENST00000695904.1		c.266-2118A>G		intron	N/A	ENSP00000512259.1
	CCBE1	ENST00000649564.1		c.266-2118A>G		intron	N/A	ENSP00000497183.1

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39171 AN: 152016 Hom.: 5599 Cov.: 33

Gnomad AFR AF: 0.371

Gnomad AMI AF: 0.368

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.219

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.222

Gnomad OTH AF: 0.249

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.258 AC: 39190 AN: 152134 Hom.: 5604 Cov.: 33 AF XY: 0.253 AC XY: 18825 AN XY: 74370

African (AFR) AF: 0.371 AC: 15381 AN: 41500

American (AMR) AF: 0.192 AC: 2938 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 808 AN: 3468

East Asian (EAS) AF: 0.218 AC: 1127 AN: 5162

South Asian (SAS) AF: 0.118 AC: 569 AN: 4814

European-Finnish (FIN) AF: 0.222 AC: 2354 AN: 10584

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.222 AC: 15075 AN: 67992

Other (OTH) AF: 0.244 AC: 516 AN: 2114

Alfa AF: 0.232 Hom.: 15070

Bravo AF: 0.265

Asia WGS AF: 0.174 AC: 606 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	8.9
DANN	Benign	0.68
PhyloP100		0.17
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs12961264; hg19: chr18-57138957;