Genetic Variant CCM2L:p.Arg26Cys (chr20-32014949-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001365692.1(CCM2L):c.76C>T(p.Arg26Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000556 in 1,601,940 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

CCM2L
NM_001365692.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.28

Variant links:

Genes affected

CCM2L (HGNC:16153): (CCM2 like scaffold protein) Predicted to act upstream of or within several processes, including heart development; negative regulation of homotypic cell-cell adhesion; and positive regulation of fibroblast growth factor production. [provided by Alliance of Genome Resources, Apr 2022]

CCM2L links:

ENSG00000226239 (HGNC:):

ENSG00000226239 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCM2L	NM_001365692.1 link	c.76C>T	p.Arg26Cys	missense_variant	Exon 2 of 10	ENST00000452892.3	NP_001352621.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CCM2L	ENST00000452892.3 link	c.76C>T	p.Arg26Cys	missense_variant	Exon 2 of 10	2	NM_001365692.1	ENSP00000392448.2	Q9NUG4-1
CCM2L	ENST00000262659.12 link	c.76C>T	p.Arg26Cys	missense_variant	Exon 2 of 9	1		ENSP00000262659.8	Q9NUG4-2
ENSG00000226239	ENST00000653258.1 link	n.705-7300G>A		intron_variant	Intron 2 of 2
ENSG00000226239	ENST00000662576.1 link	n.816-7300G>A		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000887

AC:

AN:

236886

Hom.:

AF XY:

0.000124

AC XY:

AN XY:

128836

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000625

Gnomad SAS exome

AF:

0.000537

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000375

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000566

AC:

AN:

1449760

Hom.:

Cov.:

AF XY:

0.0000818

AC XY:

AN XY:

721314

show subpopulations

Gnomad4 AFR exome

AF:

0.0000927

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000266

Gnomad4 SAS exome

AF:

0.000561

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000208

Gnomad4 OTH exome

AF:

0.0000334

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.76C>T (p.R26C) alteration is located in exon 2 (coding exon 2) of the CCM2L gene. This alteration results from a C to T substitution at nucleotide position 76, causing the arginine (R) at amino acid position 26 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.033

MetaRNN

Uncertain

0.60

MetaSVM

Benign

-0.56

MutationAssessor

Uncertain

2.3

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-4.7

REVEL

Benign

0.19

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.72

MVP

0.50

MPC

0.14

ClinPred

0.70

GERP RS

4.9

gMVP

0.38

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over