rs1554377652

Variant names:

• chr7-45069851-T-C
• rs1554377652
• NM_031443.4:c.635T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_031443.4(CCM2):​c.635T>C​(p.Leu212Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L212L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CCM2 NM_031443.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.97
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889
• PP5: Variant 7-45069851-T-C is Pathogenic according to our data. Variant chr7-45069851-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 468338.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.635T>C	p.Leu212Pro	missense	Exon 6 of 10	NP_113631.1	Q9BSQ5-1
	CCM2	NM_001363458.2		c.635T>C	p.Leu212Pro	missense	Exon 6 of 11	NP_001350387.1
	CCM2	NM_001029835.2		c.698T>C	p.Leu233Pro	missense	Exon 6 of 10	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.635T>C	p.Leu212Pro	missense	Exon 6 of 10	ENSP00000258781.7	Q9BSQ5-1
	CCM2	ENST00000477605.1	TSL:1	n.970T>C		non_coding_transcript_exon	Exon 2 of 6
	CCM2	ENST00000481194.1	TSL:1	n.70T>C		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Cerebral cavernous malformation 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		8.0
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.67		Loss of stability (P = 0.0272)
MVP		0.86
MPC		1.3
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.95
gMVP		0.90
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs1554377652; hg19: chr7-45109450;