NM_031443.4:c.30+6044A>G

Variant names:

• chr7-45006407-A-G
• rs1968075
• NM_031443.4:c.30+6044A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_031443.4(CCM2):​c.30+6044A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.867 in 151,750 control chromosomes in the GnomAD database, including 57,291 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.87 (57291 hom., cov: 28)
• Consequence: CCM2 NM_031443.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06
• Publications: 1 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.953 is higher than 0.05.

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.30+6044A>G		intron	N/A	NP_113631.1	Q9BSQ5-1
	CCM2	NM_001363458.2		c.30+6044A>G		intron	N/A	NP_001350387.1
	CCM2	NM_001363459.2		c.30+6044A>G		intron	N/A	NP_001350388.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCM2	ENST00000258781.11	TSL:1 MANE Select	c.30+6044A>G		intron	N/A	ENSP00000258781.7	Q9BSQ5-1
	CCM2	ENST00000938553.1		c.31-861A>G		intron	N/A	ENSP00000608612.1
	CCM2	ENST00000956241.1		c.30+6044A>G		intron	N/A	ENSP00000626300.1

Frequencies

GnomAD3 genomes AF: 0.866 AC: 131388 AN: 151632 Hom.: 57234 Cov.: 28

Gnomad AFR AF: 0.961

Gnomad AMI AF: 0.901

Gnomad AMR AF: 0.827

Gnomad ASJ AF: 0.776

Gnomad EAS AF: 0.909

Gnomad SAS AF: 0.856

Gnomad FIN AF: 0.878

Gnomad MID AF: 0.777

Gnomad NFE AF: 0.819

Gnomad OTH AF: 0.823

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.867 AC: 131506 AN: 151750 Hom.: 57291 Cov.: 28 AF XY: 0.869 AC XY: 64406 AN XY: 74106

African (AFR) AF: 0.961 AC: 39783 AN: 41390

American (AMR) AF: 0.828 AC: 12610 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.776 AC: 2692 AN: 3470

East Asian (EAS) AF: 0.910 AC: 4675 AN: 5140

South Asian (SAS) AF: 0.856 AC: 4110 AN: 4802

European-Finnish (FIN) AF: 0.878 AC: 9200 AN: 10480

Middle Eastern (MID) AF: 0.781 AC: 228 AN: 292

European-Non Finnish (NFE) AF: 0.819 AC: 55660 AN: 67928

Other (OTH) AF: 0.823 AC: 1730 AN: 2102

Alfa AF: 0.797 Hom.: 2661

Bravo AF: 0.871

Asia WGS AF: 0.859 AC: 2990 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.51
DANN	Benign	0.081
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs1968075; hg19: chr7-45046006;