7-45000334-A-C

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 10P and 4B. PVS1 PM2 BS2

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. 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

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 9 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
• BS2: High AC in GnomAdExome4 at 5 AD gene.

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000543

Gnomad4 OTH exome AF: 0.00

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
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.70

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-45039933;