7-45000363-G-C

Variant names:

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

Variant summary

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

The NM_031443.4(CCM2):​c.30G>C​(p.Lys10Asn) variant causes a missense, splice region 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. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. K10K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 24)
• Consequence: CCM2 NM_031443.4 missense, splice_region
• Scores: Splicing: ADA: 0.0002008
• Clinical Significance: Uncertain significance criteria provided, single submitter 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.34274793).

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>C	p.Lys10Asn	missense splice_region	Exon 1 of 10	NP_113631.1	Q9BSQ5-1
	CCM2	NM_001363458.2		c.30G>C	p.Lys10Asn	missense splice_region	Exon 1 of 11	NP_001350387.1
	CCM2	NM_001363459.2		c.30G>C	p.Lys10Asn	missense splice_region	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>C	p.Lys10Asn	missense splice_region	Exon 1 of 10	ENSP00000258781.7	Q9BSQ5-1
	CCM2	ENST00000938553.1		c.30G>C	p.Lys10Asn	missense splice_region	Exon 1 of 11	ENSP00000608612.1
	CCM2	ENST00000956241.1		c.30G>C	p.Lys10Asn	missense splice_region	Exon 1 of 12	ENSP00000626300.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.55
CADD	Pathogenic	27
DANN	Benign	0.91
DEOGEN2	Benign	0.076	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.45	T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.6
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.12
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.021	D
Polyphen		0.97	D
Vest4		0.18
MutPred		0.26		Loss of methylation at K10 (P = 9e-04)
MVP		0.66
ClinPred		0.33	T
GERP RS		1.8
PromoterAI		0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.097
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00020
dbscSNV1_RF	Benign	0.28
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: 6

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

Other links and lift over

dbSNP: rs1583819255; hg19: chr7-45039962;