rs121908252

Variant names:

• chr18-59438119-C-G
• rs121908252
• NM_133459.4:c.979G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_133459.4(CCBE1):​c.979G>C​(p.Gly327Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CCBE1 NM_133459.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 6.65
• Publications: 4 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 18-59438119-C-G is Pathogenic according to our data. Variant chr18-59438119-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 447.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCBE1	NM_133459.4	c.979G>C	p.Gly327Arg	missense_variant	Exon 10 of 11	ENST00000439986.9	NP_597716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCBE1	ENST00000439986.9	c.979G>C	p.Gly327Arg	missense_variant	Exon 10 of 11	1	NM_133459.4	ENSP00000404464.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Hennekam lymphangiectasia-lymphedema syndrome 1 Pathogenic:1 Other:1

Dec 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.45	T;T;T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.0	H;H;.
PhyloP100		6.7
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.0	D;.;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;.;D
Polyphen		1.0	D;D;.
Vest4		0.93
MutPred		0.95		Gain of methylation at G327 (P = 0.0456);Gain of methylation at G327 (P = 0.0456);.;
MVP		1.0
MPC		0.42
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.79
gMVP		0.74
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.010		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: rs121908252; hg19: chr18-57105351;