chr7-45049419-C-T

Variant names:

• chr7-45049419-C-T
• rs10280402
• NM_031443.4:c.204+10993C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_031443.4(CCM2):​c.204+10993C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 152,224 control chromosomes in the GnomAD database, including 1,661 homozygotes. 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: 𝑓 0.13 (1661 hom., cov: 32)
• Consequence: CCM2 NM_031443.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0620
• Publications: 3 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCM2	NM_031443.4	c.204+10993C>T		intron_variant	Intron 2 of 9	ENST00000258781.11	NP_113631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCM2	ENST00000258781.11	c.204+10993C>T		intron_variant	Intron 2 of 9	1	NM_031443.4	ENSP00000258781.7

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20299 AN: 152106 Hom.: 1663 Cov.: 32

Gnomad AFR AF: 0.0389

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.0904

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.177

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.133 AC: 20299 AN: 152224 Hom.: 1661 Cov.: 32 AF XY: 0.131 AC XY: 9737 AN XY: 74434

African (AFR) AF: 0.0388 AC: 1613 AN: 41548

American (AMR) AF: 0.173 AC: 2646 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 777 AN: 3470

East Asian (EAS) AF: 0.0902 AC: 468 AN: 5186

South Asian (SAS) AF: 0.143 AC: 692 AN: 4828

European-Finnish (FIN) AF: 0.122 AC: 1290 AN: 10590

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.181 AC: 12282 AN: 68002

Other (OTH) AF: 0.177 AC: 373 AN: 2110

Alfa AF: 0.155 Hom.: 262

Bravo AF: 0.129

Asia WGS AF: 0.138 AC: 480 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	5.9
DANN	Benign	0.82
PhyloP100		0.062
Mutation Taster		=100/0	polymorphism (auto)

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: rs10280402; hg19: chr7-45089018;