18-59431120-A-G

Variant names:

• chr18-59431120-A-G
• rs77728352
• NM_133459.4:c.*4788T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_133459.4(CCBE1):​c.*4788T>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 0.0372 in 152,318 control chromosomes in the GnomAD database, including 187 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (187 hom., cov: 33)
  • 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: 0.0620
• 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• 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=-0.77).
• BP6: Variant 18-59431120-A-G is Benign according to our data. Variant chr18-59431120-A-G is described in ClinVar as Benign. ClinVar VariationId is 327589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0372 (5669/152318) while in subpopulation NFE AF = 0.0472 (3213/68026). AF 95% confidence interval is 0.0459. There are 187 homozygotes in GnomAd4. There are 2966 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 187 AR gene

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.*4788T>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.*4788T>C		3_prime_UTR	Exon 11 of 11	ENSP00000404464.2	Q6UXH8-1
	CCBE1	ENST00000649564.1		c.*4788T>C		3_prime_UTR	Exon 12 of 12	ENSP00000497183.1	Q6UXH8-1
	CCBE1	ENST00000650467.2		c.*4788T>C		3_prime_UTR	Exon 9 of 9	ENSP00000496897.2	A0A3B3IRL6

Frequencies

GnomAD3 genomes AF: 0.0372 AC: 5668 AN: 152200 Hom.: 187 Cov.: 33

Gnomad AFR AF: 0.00743

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0321

Gnomad ASJ AF: 0.0597

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0472

Gnomad OTH AF: 0.0483

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: 0.0372 AC: 5669 AN: 152318 Hom.: 187 Cov.: 33 AF XY: 0.0398 AC XY: 2966 AN XY: 74486

African (AFR) AF: 0.00743 AC: 309 AN: 41578

American (AMR) AF: 0.0320 AC: 490 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0597 AC: 207 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.0182 AC: 88 AN: 4830

European-Finnish (FIN) AF: 0.115 AC: 1224 AN: 10610

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0472 AC: 3213 AN: 68026

Other (OTH) AF: 0.0478 AC: 101 AN: 2114

Alfa AF: 0.0255 Hom.: 25

Bravo AF: 0.0314

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

ClinVar submissions

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	-0.77
CADD	Benign	6.9
DANN	Benign	0.68
PhyloP100		0.062
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: rs77728352; hg19: chr18-57098352;