NM_031443.4:c.30G>A

Variant names:

• chr7-45000363-G-A
• rs1583819255
• NM_031443.4:c.30G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP5 BP4 BP7

The NM_031443.4(CCM2):​c.30G>A​(p.Lys10Lys) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CCM2 NM_031443.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0003241
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 1.60
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-45000363-G-A is Pathogenic according to our data. Variant chr7-45000363-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 662968.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68). . Strength limited to SUPPORTING due to the PP5.
• BP7: Synonymous conserved (PhyloP=1.6 with no splicing effect.

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.30G>A	p.Lys10Lys	splice_region synonymous	Exon 1 of 10	NP_113631.1	Q9BSQ5-1
	CCM2	NM_001363458.2		c.30G>A	p.Lys10Lys	splice_region synonymous	Exon 1 of 11	NP_001350387.1
	CCM2	NM_001363459.2		c.30G>A	p.Lys10Lys	splice_region synonymous	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.30G>A	p.Lys10Lys	splice_region synonymous	Exon 1 of 10	ENSP00000258781.7	Q9BSQ5-1
	CCM2	ENST00000938553.1		c.30G>A	p.Lys10Lys	splice_region synonymous	Exon 1 of 11	ENSP00000608612.1
	CCM2	ENST00000956241.1		c.30G>A	p.Lys10Lys	splice_region synonymous	Exon 1 of 12	ENSP00000626300.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1157446 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 559088

African (AFR) AF: 0.00 AC: 0 AN: 24230

American (AMR) AF: 0.00 AC: 0 AN: 15548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17848

East Asian (EAS) AF: 0.00 AC: 0 AN: 27060

South Asian (SAS) AF: 0.00 AC: 0 AN: 32766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38008

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3200

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 952496

Other (OTH) AF: 0.00 AC: 0 AN: 46290

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	not provided (2)
1	-	-	Cerebral cavernous malformation 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	21
DANN	Benign	0.92
PhyloP100		1.6
PromoterAI		-0.089	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=74/26	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00032
dbscSNV1_RF	Benign	0.62
SpliceAI score (max)		0.19		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: rs1583819255; hg19: chr7-45039962;