rs4940876

Variant names:

• chr18-59466920-A-G
• rs4940876
• NM_133459.4:c.401-29T>C

Your query was ambiguous. Multiple possible variants found:

• chr18-59466920-A-G
• chr18-59466920-A-T

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.401-29T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.992 in 1,598,734 control chromosomes in the GnomAD database, including 787,955 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.96 (70644 hom., cov: 34)
  • Exomes 𝑓: 1.0 (717311 hom.)
• Consequence: CCBE1 NM_133459.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.566
• Publications: 8 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 18-59466920-A-G is Benign according to our data. Variant chr18-59466920-A-G is described in ClinVar as Benign. ClinVar VariationId is 262353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 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.401-29T>C		intron	N/A	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.401-29T>C		intron	N/A	ENSP00000404464.2	Q6UXH8-1
	CCBE1	ENST00000695904.1		c.401-29T>C		intron	N/A	ENSP00000512259.1	A0A8Q3WKU1
	CCBE1	ENST00000649564.1		c.401-29T>C		intron	N/A	ENSP00000497183.1	Q6UXH8-1

Frequencies

GnomAD3 genomes AF: 0.962 AC: 146348 AN: 152208 Hom.: 70593 Cov.: 34

Gnomad AFR AF: 0.868

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.985

Gnomad ASJ AF: 0.992

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.984

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.967

GnomAD2 exomes AF: 0.989 AC: 248218 AN: 250914 AF XY: 0.992

Gnomad AFR exome AF: 0.867

Gnomad AMR exome AF: 0.991

Gnomad ASJ exome AF: 0.992

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.993

GnomAD4 exome AF: 0.996 AC: 1440192 AN: 1446408 Hom.: 717311 Cov.: 25 AF XY: 0.996 AC XY: 717785 AN XY: 720536

African (AFR) AF: 0.871 AC: 28855 AN: 33136

American (AMR) AF: 0.991 AC: 44203 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.990 AC: 25676 AN: 25938

East Asian (EAS) AF: 1.00 AC: 39456 AN: 39456

South Asian (SAS) AF: 1.00 AC: 85874 AN: 85900

European-Finnish (FIN) AF: 1.00 AC: 52752 AN: 52754

Middle Eastern (MID) AF: 0.989 AC: 4996 AN: 5052

European-Non Finnish (NFE) AF: 0.999 AC: 1099271 AN: 1099892

Other (OTH) AF: 0.991 AC: 59109 AN: 59666

GnomAD4 genome AF: 0.961 AC: 146459 AN: 152326 Hom.: 70644 Cov.: 34 AF XY: 0.963 AC XY: 71718 AN XY: 74490

African (AFR) AF: 0.868 AC: 36072 AN: 41544

American (AMR) AF: 0.985 AC: 15087 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.992 AC: 3445 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5188 AN: 5188

South Asian (SAS) AF: 0.999 AC: 4827 AN: 4832

European-Finnish (FIN) AF: 1.00 AC: 10620 AN: 10620

Middle Eastern (MID) AF: 0.983 AC: 289 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67978 AN: 68044

Other (OTH) AF: 0.967 AC: 2041 AN: 2110

Alfa AF: 0.968 Hom.: 15436

Bravo AF: 0.956

Asia WGS AF: 0.992 AC: 3449 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.6
DANN	Benign	0.75
PhyloP100		-0.57
BranchPoint Hunter		1.0
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: rs4940876; hg19: chr18-57134152;