NM_031443.4:c.17A>G

Variant names:

• chr7-45000350-A-G
• NM_031443.4:c.17A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031443.4(CCM2):​c.17A>G​(p.Lys6Arg) variant causes a missense 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 8.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CCM2 NM_031443.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0370
• 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), ClinGen, Genomics England PanelApp
• famililal cerebral cavernous malformations

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.097101).

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.17A>G	p.Lys6Arg	missense	Exon 1 of 10	NP_113631.1	Q9BSQ5-1
	CCM2	NM_001363458.2		c.17A>G	p.Lys6Arg	missense	Exon 1 of 11	NP_001350387.1
	CCM2	NM_001363459.2		c.17A>G	p.Lys6Arg	missense	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.17A>G	p.Lys6Arg	missense	Exon 1 of 10	ENSP00000258781.7	Q9BSQ5-1
	CCM2	ENST00000938553.1		c.17A>G	p.Lys6Arg	missense	Exon 1 of 11	ENSP00000608612.1
	CCM2	ENST00000956241.1		c.17A>G	p.Lys6Arg	missense	Exon 1 of 12	ENSP00000626300.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 8.81e-7 AC: 1 AN: 1135160 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 547962

⚠️ 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: 23508

American (AMR) AF: 0.00 AC: 0 AN: 14232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16996

East Asian (EAS) AF: 0.00 AC: 0 AN: 25430

South Asian (SAS) AF: 0.00 AC: 0 AN: 31580

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35978

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3086

European-Non Finnish (NFE) AF: 0.00000106 AC: 1 AN: 939496

Other (OTH) AF: 0.00 AC: 0 AN: 44854

⚠️ 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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.0099	N
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.037
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.072
Sift	Benign	0.50	T
Sift4G	Benign	0.21	T
Polyphen		0.0	B
Vest4		0.088
MutPred		0.12		Loss of methylation at K6 (P = 0.0181)
MVP		0.56
ClinPred		0.051	T
GERP RS		-0.20
PromoterAI		0.010	Neutral
Varity_R		0.055
Mutation Taster		=91/9	polymorphism

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

hg19: chr7-45039949;