rs4940465

Variant names:

• chr18-59506612-T-C
• rs4940465
• NM_133459.4:c.213-26374A>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.213-26374A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.263 in 152,102 control chromosomes in the GnomAD database, including 5,504 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 (5504 hom., cov: 32)
• Consequence: CCBE1 NM_133459.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.25
• Publications: 0 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 (EAS) allele frequency at 95% confidence interval = 0.283 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.213-26374A>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.213-26374A>G		intron	N/A	ENSP00000404464.2
	CCBE1	ENST00000695904.1		c.213-26374A>G		intron	N/A	ENSP00000512259.1
	CCBE1	ENST00000649564.1		c.213-26374A>G		intron	N/A	ENSP00000497183.1

Frequencies

GnomAD3 genomes AF: 0.264 AC: 40056 AN: 151984 Hom.: 5502 Cov.: 32

Gnomad AFR AF: 0.247

Gnomad AMI AF: 0.410

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.253

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.274

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

GnomAD4 genome AF: 0.263 AC: 40067 AN: 152102 Hom.: 5504 Cov.: 32 AF XY: 0.260 AC XY: 19319 AN XY: 74352

African (AFR) AF: 0.247 AC: 10256 AN: 41500

American (AMR) AF: 0.229 AC: 3495 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 993 AN: 3468

East Asian (EAS) AF: 0.295 AC: 1522 AN: 5162

South Asian (SAS) AF: 0.178 AC: 858 AN: 4824

European-Finnish (FIN) AF: 0.253 AC: 2676 AN: 10576

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.283 AC: 19221 AN: 67964

Other (OTH) AF: 0.271 AC: 572 AN: 2112

Alfa AF: 0.280 Hom.: 10977

Bravo AF: 0.265

Asia WGS AF: 0.228 AC: 794 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	0.38
DANN	Benign	0.69
PhyloP100		-1.2
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: rs4940465; hg19: chr18-57173844; COSMIC: COSV71671253;