NM_031443.4:c.384G>T

Variant names:

• chr7-45064558-G-T
• rs73694268
• NM_031443.4:c.384G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_031443.4(CCM2):​c.384G>T​(p.Glu128Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E128E) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CCM2 NM_031443.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.278
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_031443.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28696853).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCM2	NM_031443.4	MANE Select	c.384G>T	p.Glu128Asp	missense	Exon 4 of 10	NP_113631.1
	CCM2	NM_001363458.2		c.384G>T	p.Glu128Asp	missense	Exon 4 of 11	NP_001350387.1
	CCM2	NM_001029835.2		c.447G>T	p.Glu149Asp	missense	Exon 4 of 10	NP_001025006.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCM2	ENST00000258781.11	TSL:1 MANE Select	c.384G>T	p.Glu128Asp	missense	Exon 4 of 10	ENSP00000258781.7
	CCM2	ENST00000381112.7	TSL:2	c.447G>T	p.Glu149Asp	missense	Exon 4 of 10	ENSP00000370503.3
	CCM2	ENST00000475551.5	TSL:2	c.366G>T	p.Glu122Asp	missense	Exon 4 of 10	ENSP00000417180.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461724 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727168

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	0.00036	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Benign	0.057
Eigen_PC	Benign	0.045
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.28
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.028	D
Polyphen		0.012	B
Vest4		0.49
MutPred		0.55		Loss of stability (P = 0.3195)
MVP		0.44
MPC		0.87
ClinPred		0.90	D
GERP RS		0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.52
gMVP		0.43
Mutation Taster		=31/69	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: rs73694268; hg19: chr7-45104157;