18-59431404-C-G

Variant names:

• chr18-59431404-C-G
• rs7230906
• NM_133459.4:c.*4504G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_133459.4(CCBE1):​c.*4504G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 152,066 control chromosomes in the GnomAD database, including 12,715 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12714 hom., cov: 33)
  • Exomes 𝑓: 0.50 (1 hom.)
• Consequence: CCBE1 NM_133459.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.623
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 18-59431404-C-G is Benign according to our data. Variant chr18-59431404-C-G is described in ClinVar as Benign. ClinVar VariationId is 327594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.652 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.*4504G>C		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.*4504G>C		3_prime_UTR	Exon 11 of 11	ENSP00000404464.2	Q6UXH8-1
	CCBE1	ENST00000649564.1		c.*4504G>C		3_prime_UTR	Exon 12 of 12	ENSP00000497183.1	Q6UXH8-1
	CCBE1	ENST00000650467.2		c.*4504G>C		3_prime_UTR	Exon 9 of 9	ENSP00000496897.2	A0A3B3IRL6

Frequencies

GnomAD3 genomes AF: 0.396 AC: 60201 AN: 151944 Hom.: 12712 Cov.: 33

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.589

Gnomad AMR AF: 0.441

Gnomad ASJ AF: 0.388

Gnomad EAS AF: 0.670

Gnomad SAS AF: 0.497

Gnomad FIN AF: 0.508

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.428

Gnomad OTH AF: 0.409

GnomAD4 exome AF: 0.500 AC: 2 AN: 4 Hom.: 1 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

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) AF: 0.500 AC: 2 AN: 4

GnomAD4 genome AF: 0.396 AC: 60214 AN: 152062 Hom.: 12714 Cov.: 33 AF XY: 0.403 AC XY: 29968 AN XY: 74318

African (AFR) AF: 0.250 AC: 10348 AN: 41474

American (AMR) AF: 0.441 AC: 6737 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.388 AC: 1343 AN: 3464

East Asian (EAS) AF: 0.670 AC: 3472 AN: 5180

South Asian (SAS) AF: 0.496 AC: 2389 AN: 4818

European-Finnish (FIN) AF: 0.508 AC: 5354 AN: 10544

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.428 AC: 29077 AN: 67990

Other (OTH) AF: 0.408 AC: 862 AN: 2112

Alfa AF: 0.415 Hom.: 1697

Bravo AF: 0.384

Asia WGS AF: 0.536 AC: 1865 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	-0.82
CADD	Benign	5.0
DANN	Benign	0.48
PhyloP100		0.62
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: rs7230906; hg19: chr18-57098636;