20-32018949-G-A

Position:

• chr20-32018949-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001365692.1(CCM2L):​c.473G>A​(p.Gly158Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000225 in 1,245,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: CCM2L NM_001365692.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.18

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29470062).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCM2L	NM_001365692.1	c.473G>A	p.Gly158Asp	missense_variant	5/10	ENST00000452892.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCM2L	ENST00000452892.3	c.473G>A	p.Gly158Asp	missense_variant	5/10	2	NM_001365692.1	P1
CCM2L	ENST00000262659.12	c.473G>A	p.Gly158Asp	missense_variant	5/9	1
	ENST00000662576.1	n.815+9979C>T		intron_variant, non_coding_transcript_variant
	ENST00000653258.1	n.704+9979C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000225 AC: 28 AN: 1245906 Hom.: 0 Cov.: 31 AF XY: 0.0000163 AC XY: 10 AN XY: 612588

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000267

Gnomad4 OTH exome AF: 0.0000197

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2022

The c.473G>A (p.G158D) alteration is located in exon 5 (coding exon 5) of the CCM2L gene. This alteration results from a G to A substitution at nucleotide position 473, causing the glycine (G) at amino acid position 158 to be replaced by an aspartic acid (D). 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	Pathogenic	0.80
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Uncertain	0.98
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.71	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.77	N
MutationTaster	Benign	0.80	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.20
Sift	Benign	0.087	T
Sift4G	Uncertain	0.011	D
Polyphen		0.42	B
Vest4		0.29
MutPred		0.23		Loss of catalytic residue at V159 (P = 0.063);
MVP		0.49
MPC		1.1
ClinPred		0.53	D
GERP RS		3.4
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

Other links and lift over

dbSNP: rs1387461995; hg19: chr20-30606752;