NM_031443.4:c.30+17G>A

Variant names:

• chr7-45000380-G-A
• rs557904216
• NM_031443.4:c.30+17G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_031443.4(CCM2):​c.30+17G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000263 in 1,139,650 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.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: CCM2 NM_031443.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.30
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).

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.30+17G>A		intron	N/A	NP_113631.1
	CCM2	NM_001363458.2		c.30+17G>A		intron	N/A	NP_001350387.1
	CCM2	NM_001363459.2		c.30+17G>A		intron	N/A	NP_001350388.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCM2	ENST00000258781.11	TSL:1 MANE Select	c.30+17G>A		intron	N/A	ENSP00000258781.7
	CCM2	ENST00000541586.5	TSL:3	c.30+17G>A		intron	N/A	ENSP00000444725.1
	CCM2	ENST00000544363.5	TSL:3	c.30+17G>A		intron	N/A	ENSP00000438035.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000263 AC: 3 AN: 1139650 Hom.: 0 Cov.: 31 AF XY: 0.00000364 AC XY: 2 AN XY: 548770

⚠️ 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: 23680

American (AMR) AF: 0.00 AC: 0 AN: 13098

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16714

East Asian (EAS) AF: 0.00 AC: 0 AN: 26838

South Asian (SAS) AF: 0.00 AC: 0 AN: 29858

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3128

European-Non Finnish (NFE) AF: 0.00000318 AC: 3 AN: 943696

Other (OTH) AF: 0.00 AC: 0 AN: 45442

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000568638), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	9.5
DANN	Benign	0.95
PhyloP100		1.3
PromoterAI		0.066	Neutral

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: rs557904216; hg19: chr7-45039979;