rs61745250

Variant names:

• chr18-59439755-G-A
• rs61745250
• NM_133459.4:c.837C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_133459.4(CCBE1):​c.837C>T​(p.Pro279Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0159 in 1,614,160 control chromosomes in the GnomAD database, including 252 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (17 hom., cov: 33)
  • Exomes 𝑓: 0.016 (235 hom.)
• Consequence: CCBE1 NM_133459.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.36
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 18-59439755-G-A is Benign according to our data. Variant chr18-59439755-G-A is described in ClinVar as Benign. ClinVar VariationId is 262356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.36 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0115 (1751/152328) while in subpopulation NFE AF = 0.0191 (1297/68026). AF 95% confidence interval is 0.0182. There are 17 homozygotes in GnomAd4. There are 824 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 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.837C>T	p.Pro279Pro	synonymous	Exon 8 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.837C>T	p.Pro279Pro	synonymous	Exon 8 of 11	ENSP00000404464.2	Q6UXH8-1
	CCBE1	ENST00000589116.2	TSL:1	n.545C>T		non_coding_transcript_exon	Exon 3 of 6
	CCBE1	ENST00000695904.1		c.950C>T	p.Pro317Leu	missense	Exon 8 of 11	ENSP00000512259.1	A0A8Q3WKU1

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1753 AN: 152210 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.00340

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00883

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0111

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0191

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.0121 AC: 3026 AN: 250740 AF XY: 0.0120

Gnomad AFR exome AF: 0.00268

Gnomad AMR exome AF: 0.00587

Gnomad ASJ exome AF: 0.00766

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0115

Gnomad NFE exome AF: 0.0204

Gnomad OTH exome AF: 0.0110

GnomAD4 exome AF: 0.0163 AC: 23898 AN: 1461832 Hom.: 235 Cov.: 32 AF XY: 0.0158 AC XY: 11526 AN XY: 727216

African (AFR) AF: 0.00182 AC: 61 AN: 33480

American (AMR) AF: 0.00566 AC: 253 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00750 AC: 196 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00297 AC: 256 AN: 86254

European-Finnish (FIN) AF: 0.0118 AC: 628 AN: 53416

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5760

European-Non Finnish (NFE) AF: 0.0195 AC: 21724 AN: 1111978

Other (OTH) AF: 0.0128 AC: 775 AN: 60394

GnomAD4 genome AF: 0.0115 AC: 1751 AN: 152328 Hom.: 17 Cov.: 33 AF XY: 0.0111 AC XY: 824 AN XY: 74496

African (AFR) AF: 0.00339 AC: 141 AN: 41576

American (AMR) AF: 0.00875 AC: 134 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4828

European-Finnish (FIN) AF: 0.0111 AC: 118 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0191 AC: 1297 AN: 68026

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.0154 Hom.: 7

Bravo AF: 0.0100

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0167

EpiControl AF: 0.0168

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hennekam lymphangiectasia-lymphedema syndrome 1 (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.96
DANN	Benign	0.55
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism

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: rs61745250; hg19: chr18-57106987;