NM_031443.4:c.-27_-19dupCGGGCCGCG

Variant names:

• chr7-45000305-G-GGCGGGCCGC
• rs1207990370
• NM_031443.4:c.-27_-19dupCGGGCCGCG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_031443.4(CCM2):​c.-27_-19dupCGGGCCGCG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000135 in 148,542 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 25)
  • Exomes 𝑓: 0.0000018 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CCM2 NM_031443.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0110
• Publications: 0 publications found

Genes affected

CCM2 (HGNC:21708): (CCM2 scaffold protein) This gene encodes a scaffold protein that functions in the stress-activated p38 Mitogen-activated protein kinase (MAPK) signaling cascade. The protein interacts with SMAD specific E3 ubiquitin protein ligase 1 (also known as SMURF1) via a phosphotyrosine binding domain to promote RhoA degradation. The protein is required for normal cytoskeletal structure, cell-cell interactions, and lumen formation in endothelial cells. Mutations in this gene result in cerebral cavernous malformations. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Nov 2009]

CCM2 Gene-Disease associations (from GenCC):

• cerebral cavernous malformation 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
• famililal cerebral cavernous malformations

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 7-45000305-G-GGCGGGCCGC is Benign according to our data. Variant chr7-45000305-G-GGCGGGCCGC is described in ClinVar as Likely_benign. ClinVar VariationId is 421825.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031443.4. 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
	CCM2	NM_031443.4	MANE Select	c.-27_-19dupCGGGCCGCG		5_prime_UTR	Exon 1 of 10	NP_113631.1	Q9BSQ5-1
	CCM2	NM_001363458.2		c.-27_-19dupCGGGCCGCG		5_prime_UTR	Exon 1 of 11	NP_001350387.1
	CCM2	NM_001363459.2		c.-27_-19dupCGGGCCGCG		5_prime_UTR	Exon 1 of 10	NP_001350388.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCM2	ENST00000258781.11	TSL:1 MANE Select	c.-27_-19dupCGGGCCGCG		5_prime_UTR	Exon 1 of 10	ENSP00000258781.7	Q9BSQ5-1
	CCM2	ENST00000938553.1		c.-27_-19dupCGGGCCGCG		5_prime_UTR	Exon 1 of 11	ENSP00000608612.1
	CCM2	ENST00000956241.1		c.-27_-19dupCGGGCCGCG		5_prime_UTR	Exon 1 of 12	ENSP00000626300.1

Frequencies

GnomAD3 genomes AF: 0.0000135 AC: 2 AN: 148542 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000301

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000181 AC: 2 AN: 1105272 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 529370

African (AFR) AF: 0.00 AC: 0 AN: 22782

American (AMR) AF: 0.00 AC: 0 AN: 10390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14448

East Asian (EAS) AF: 0.00 AC: 0 AN: 25820

South Asian (SAS) AF: 0.00 AC: 0 AN: 23528

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34636

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2980

European-Non Finnish (NFE) AF: 0.00000216 AC: 2 AN: 927074

Other (OTH) AF: 0.00 AC: 0 AN: 43614

GnomAD4 genome AF: 0.0000135 AC: 2 AN: 148542 Hom.: 0 Cov.: 25 AF XY: 0.0000276 AC XY: 2 AN XY: 72344

African (AFR) AF: 0.00 AC: 0 AN: 40938

American (AMR) AF: 0.00 AC: 0 AN: 14980

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3396

East Asian (EAS) AF: 0.00 AC: 0 AN: 5094

South Asian (SAS) AF: 0.00 AC: 0 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9694

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000301 AC: 2 AN: 66380

Other (OTH) AF: 0.00 AC: 0 AN: 2050

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.011

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1207990370; hg19: chr7-45039904;