chr7-45012753-T-C

Variant names:

• chr7-45012753-T-C
• rs4724344
• NM_031443.4:c.30+12390T>C

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+12390T>C 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 151,606 control chromosomes in the GnomAD database, including 57,327 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 (57327 hom., cov: 26)
• Consequence: CCM2 NM_031443.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.25
• 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.955 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+12390T>C		intron	N/A	NP_113631.1	Q9BSQ5-1
	CCM2	NM_001363458.2		c.30+12390T>C		intron	N/A	NP_001350387.1
	CCM2	NM_001363459.2		c.30+12390T>C		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+12390T>C		intron	N/A	ENSP00000258781.7	Q9BSQ5-1
	CCM2	ENST00000938553.1		c.195+5321T>C		intron	N/A	ENSP00000608612.1
	CCM2	ENST00000956241.1		c.30+12390T>C		intron	N/A	ENSP00000626300.1

Frequencies

GnomAD3 genomes AF: 0.867 AC: 131363 AN: 151488 Hom.: 57269 Cov.: 26

Gnomad AFR AF: 0.963

Gnomad AMI AF: 0.900

Gnomad AMR AF: 0.828

Gnomad ASJ AF: 0.776

Gnomad EAS AF: 0.909

Gnomad SAS AF: 0.857

Gnomad FIN AF: 0.879

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.819

Gnomad OTH AF: 0.824

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

GnomAD4 genome AF: 0.867 AC: 131482 AN: 151606 Hom.: 57327 Cov.: 26 AF XY: 0.870 AC XY: 64395 AN XY: 74030

African (AFR) AF: 0.963 AC: 39826 AN: 41344

American (AMR) AF: 0.828 AC: 12577 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.776 AC: 2693 AN: 3472

East Asian (EAS) AF: 0.910 AC: 4681 AN: 5146

South Asian (SAS) AF: 0.857 AC: 4089 AN: 4772

European-Finnish (FIN) AF: 0.879 AC: 9216 AN: 10484

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

European-Non Finnish (NFE) AF: 0.819 AC: 55618 AN: 67886

Other (OTH) AF: 0.824 AC: 1734 AN: 2104

Alfa AF: 0.845 Hom.: 7051

Bravo AF: 0.872

Asia WGS AF: 0.860 AC: 2993 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.88
DANN	Benign	0.75
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4724344; hg19: chr7-45052352; COSMIC: COSV51849429;