chr7-45000334-A-G

Variant names:

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

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

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]

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 46 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 id is 2684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCM2	NM_031443.4	c.1A>G	p.Met1?	start_lost	Exon 1 of 10	ENST00000258781.11	NP_113631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCM2	ENST00000258781.11	c.1A>G	p.Met1?	start_lost	Exon 1 of 10	1	NM_031443.4	ENSP00000258781.7

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 = 0.095309), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 25

Alfa AF: 0.000603 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cerebral cavernous malformation 2 Pathogenic:2

Jul 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the CCM2 mRNA. The next in-frame methionine is located at codon 303. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with cerebral cavernous malformations (PMID: 14740320; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2684). This variant disrupts a region of the CCM2 protein in which other variant(s) (p.Leu212Pro) have been determined to be pathogenic (PMID: 27792856; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Feb 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Mar 22, 2017

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Benign	-0.93	T
PROVEAN	Uncertain	-2.6	D;D;N
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D;D;T
Sift4G	Pathogenic	0.0	D;D;T
Polyphen		0.0020	B;.;.
Vest4		0.45
MutPred		0.55		Loss of ubiquitination at K6 (P = 0.1351);Loss of ubiquitination at K6 (P = 0.1351);Loss of ubiquitination at K6 (P = 0.1351);
MVP		0.47
ClinPred		0.53	D
GERP RS		0.14
PromoterAI		-0.073
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

Publications

LitVar

Other links and lift over

dbSNP: rs137852842; hg19: chr7-45039933;