rs137852842

Variant names:

• chr7-45000334-A-G
• rs137852842
• NM_031443.4:c.1A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-45000334-A-G
• chr7-45000334-A-C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_031443.4(CCM2):​c.1A>G​(p.Met1?) variant causes a start lost 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. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000027 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CCM2 NM_031443.4 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.436
• 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 78 pathogenic variants. Next in-frame start position is after 303 codons. Genomic position: 45073563. Lost 0.679 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-45000334-A-G is Pathogenic according to our data. Variant chr7-45000334-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 2684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1A>G	p.Met1?	start_lost	Exon 1 of 10	NP_113631.1	Q9BSQ5-1
	CCM2	NM_001363458.2		c.1A>G	p.Met1?	start_lost	Exon 1 of 11	NP_001350387.1
	CCM2	NM_001363459.2		c.1A>G	p.Met1?	start_lost	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.1A>G	p.Met1?	start_lost	Exon 1 of 10	ENSP00000258781.7	Q9BSQ5-1
	CCM2	ENST00000938553.1		c.1A>G	p.Met1?	start_lost	Exon 1 of 11	ENSP00000608612.1
	CCM2	ENST00000956241.1		c.1A>G	p.Met1?	start_lost	Exon 1 of 12	ENSP00000626300.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000272 AC: 3 AN: 1103646 Hom.: 0 Cov.: 31 AF XY: 0.00000376 AC XY: 2 AN XY: 531494

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22630

American (AMR) AF: 0.00 AC: 0 AN: 12694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15606

East Asian (EAS) AF: 0.00 AC: 0 AN: 23042

South Asian (SAS) AF: 0.00 AC: 0 AN: 28904

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33674

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2956

European-Non Finnish (NFE) AF: 0.00000326 AC: 3 AN: 921126

Other (OTH) AF: 0.00 AC: 0 AN: 43014

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0953088), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 25

Alfa AF: 0.000603 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Cerebral cavernous malformation 2 (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.0031	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.93	T
PhyloP100		0.44
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0020	B
Vest4		0.45
MutPred		0.55		Loss of ubiquitination at K6 (P = 0.1351)
MVP		0.47
ClinPred		0.53	D
GERP RS		0.14
PromoterAI		-0.073	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.64
Mutation Taster		=15/185	disease causing (ClinVar)

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: rs137852842; hg19: chr7-45039933;