CCM2 p.Ala117Ala

Variant names:

• chr7-45064522-T-T
• NM_031443.4:c.

Your query was ambiguous. Multiple possible variants found:

• chr7-45064523--
• chr7-45064525-G-T
• chr7-45064525-G-C
• chr7-45064525-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_031443.4(CCM2):​c. variant causes a intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CCM2 NM_031443.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.95
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.		intron	N/A	NP_113631.1	Q9BSQ5-1
	CCM2	NM_001363458.2		c.		intron	N/A	NP_001350387.1
	CCM2	NM_001029835.2		c.		intron	N/A	NP_001025006.1	Q9BSQ5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCM2	ENST00000258781.11	TSL:1 MANE Select	c.		intron	N/A	ENSP00000258781.7	Q9BSQ5-1
	CCM2	ENST00000481194.1	TSL:1	n.		intron	N/A
	CCM2	ENST00000938553.1		c.		intron	N/A	ENSP00000608612.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10

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

hg19: chr7-45104121;