chr7-45000334-A-C

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The NM_031443.4(CCM2):​c.1A>C​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000453 in 1,103,632 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000045 (0 hom.)
• Consequence: CCM2 NM_031443.4 initiator_codon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.436
• Publications: 0 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), Genomics England PanelApp
• famililal cerebral cavernous malformations

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 77 pathogenic variants. Next in-frame start position is after 303 codons. Genomic position: 45073563. Lost 0.679 part of the original CDS.
• PS1: Another start lost variant in NM_031443.4 (CCM2) was described as [Pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCM2	NM_031443.4	c.1A>C	p.Met1?	initiator_codon_variant	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>C	p.Met1?	initiator_codon_variant	Exon 1 of 10	1	NM_031443.4	ENSP00000258781.7

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000453 AC: 5 AN: 1103632 Hom.: 0 Cov.: 31 AF XY: 0.00000753 AC XY: 4 AN XY: 531488

⚠️ 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: 23036

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33670

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

European-Non Finnish (NFE) AF: 0.00000543 AC: 5 AN: 921122

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	19
DANN	Benign	0.73
DEOGEN2	Benign	0.22	T;.;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.0024	N
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Benign	-0.98	T
PhyloP100		0.44
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D;D;T
Sift4G	Pathogenic	0.0	D;D;T
Polyphen		0.0	B;.;.
Vest4		0.60
MutPred		0.57		Loss of methylation at K6 (P = 0.0781);Loss of methylation at K6 (P = 0.0781);Loss of methylation at K6 (P = 0.0781);
MVP		0.42
ClinPred		0.27	T
GERP RS		0.14
PromoterAI		-0.062	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.70
Mutation Taster		=15/185	disease causing

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;