NM_031443.4:c.31-10835A>G

Variant names:

• chr7-45027418-A-G
• rs1294962
• NM_031443.4:c.31-10835A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_031443.4(CCM2):​c.31-10835A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.848 in 517,936 control chromosomes in the GnomAD database, including 186,933 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.87 (57580 hom., cov: 32)
  • Exomes 𝑓: 0.84 (129353 hom.)
• Consequence: CCM2 NM_031443.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.676
• Publications: 9 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 7-45027418-A-G is Benign according to our data. Variant chr7-45027418-A-G is described in ClinVar as Benign. ClinVar VariationId is 1278177.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.956 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.31-10835A>G		intron	N/A	NP_113631.1	Q9BSQ5-1
	CCM2	NM_001363458.2		c.31-10835A>G		intron	N/A	NP_001350387.1
	CCM2	NM_001363459.2		c.30+27055A>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.31-10835A>G		intron	N/A	ENSP00000258781.7	Q9BSQ5-1
	CCM2	ENST00000475551.5	TSL:2	c.-368A>G		5_prime_UTR	Exon 1 of 10	ENSP00000417180.1	A0A0A0MT72
	CCM2	ENST00000938553.1		c.196-10835A>G		intron	N/A	ENSP00000608612.1

Frequencies

GnomAD3 genomes AF: 0.867 AC: 131934 AN: 152130 Hom.: 57522 Cov.: 32

Gnomad AFR AF: 0.963

Gnomad AMI AF: 0.900

Gnomad AMR AF: 0.826

Gnomad ASJ AF: 0.776

Gnomad EAS AF: 0.910

Gnomad SAS AF: 0.858

Gnomad FIN AF: 0.879

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.820

Gnomad OTH AF: 0.824

GnomAD4 exome AF: 0.839 AC: 306932 AN: 365688 Hom.: 129353 Cov.: 3 AF XY: 0.838 AC XY: 163429 AN XY: 194940

African (AFR) AF: 0.965 AC: 10240 AN: 10614

American (AMR) AF: 0.850 AC: 13596 AN: 15986

Ashkenazi Jewish (ASJ) AF: 0.784 AC: 8470 AN: 10806

East Asian (EAS) AF: 0.923 AC: 20817 AN: 22564

South Asian (SAS) AF: 0.859 AC: 37366 AN: 43480

European-Finnish (FIN) AF: 0.876 AC: 18822 AN: 21498

Middle Eastern (MID) AF: 0.811 AC: 1262 AN: 1556

European-Non Finnish (NFE) AF: 0.819 AC: 178857 AN: 218320

Other (OTH) AF: 0.839 AC: 17502 AN: 20864

GnomAD4 genome AF: 0.867 AC: 132053 AN: 152248 Hom.: 57580 Cov.: 32 AF XY: 0.870 AC XY: 64744 AN XY: 74440

African (AFR) AF: 0.963 AC: 40043 AN: 41564

American (AMR) AF: 0.826 AC: 12623 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.776 AC: 2693 AN: 3470

East Asian (EAS) AF: 0.910 AC: 4720 AN: 5186

South Asian (SAS) AF: 0.858 AC: 4137 AN: 4824

European-Finnish (FIN) AF: 0.879 AC: 9313 AN: 10600

Middle Eastern (MID) AF: 0.779 AC: 229 AN: 294

European-Non Finnish (NFE) AF: 0.820 AC: 55733 AN: 68002

Other (OTH) AF: 0.824 AC: 1741 AN: 2112

Alfa AF: 0.833 Hom.: 207939

Bravo AF: 0.872

Asia WGS AF: 0.863 AC: 3002 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.6
DANN	Benign	0.58
PhyloP100		0.68
PromoterAI		-0.0094	Neutral
Mutation Taster		=300/0	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: rs1294962; hg19: chr7-45067017;