rs148244188

Variant names:

• chr7-45063959-C-T
• rs148244188
• NM_031443.4:c.246C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_031443.4(CCM2):​c.246C>T​(p.Pro82Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00259 in 1,613,334 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (14 hom.)
• Consequence: CCM2 NM_031443.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0720
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 7-45063959-C-T is Benign according to our data. Variant chr7-45063959-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.072 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00175 (267/152202) while in subpopulation NFE AF = 0.00298 (203/68008). AF 95% confidence interval is 0.00265. There are 0 homozygotes in GnomAd4. There are 122 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 267 AD gene.

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.246C>T	p.Pro82Pro	synonymous	Exon 3 of 10	NP_113631.1	Q9BSQ5-1
	CCM2	NM_001363458.2		c.246C>T	p.Pro82Pro	synonymous	Exon 3 of 11	NP_001350387.1
	CCM2	NM_001029835.2		c.309C>T	p.Pro103Pro	synonymous	Exon 3 of 10	NP_001025006.1	Q9BSQ5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCM2	ENST00000258781.11	TSL:1 MANE Select	c.246C>T	p.Pro82Pro	synonymous	Exon 3 of 10	ENSP00000258781.7	Q9BSQ5-1
	CCM2	ENST00000938553.1		c.411C>T	p.Pro137Pro	synonymous	Exon 4 of 11	ENSP00000608612.1
	CCM2	ENST00000956241.1		c.246C>T	p.Pro82Pro	synonymous	Exon 3 of 12	ENSP00000626300.1

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 267 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00298

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.00186 AC: 468 AN: 251466 AF XY: 0.00188

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00268

Gnomad NFE exome AF: 0.00299

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00268 AC: 3917 AN: 1461132 Hom.: 14 Cov.: 30 AF XY: 0.00265 AC XY: 1929 AN XY: 726916

African (AFR) AF: 0.000359 AC: 12 AN: 33468

American (AMR) AF: 0.000492 AC: 22 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00153 AC: 40 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86254

European-Finnish (FIN) AF: 0.00271 AC: 145 AN: 53418

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.00317 AC: 3522 AN: 1111298

Other (OTH) AF: 0.00217 AC: 131 AN: 60372

GnomAD4 genome AF: 0.00175 AC: 267 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.00164 AC XY: 122 AN XY: 74414

African (AFR) AF: 0.000409 AC: 17 AN: 41522

American (AMR) AF: 0.000196 AC: 3 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3468

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00264 AC: 28 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00298 AC: 203 AN: 68008

Other (OTH) AF: 0.000475 AC: 1 AN: 2104

Alfa AF: 0.00283 Hom.: 0

Bravo AF: 0.00172

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00311

EpiControl AF: 0.00231

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Cerebral cavernous malformation 2 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	7.1
DANN	Benign	0.56
PhyloP100		0.072
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.010		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: rs148244188; hg19: chr7-45103558;