chr20-32019006-C-A

Position:

• chr20-32019006-C-A

Variant summary

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

The NM_001365692.1(CCM2L):​c.530C>A​(p.Pro177His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000838 in 1,193,226 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 33)
  • Exomes 𝑓: 8.4e-7 (0 hom.)
• Consequence: CCM2L NM_001365692.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.23

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=0.30310905).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCM2L	NM_001365692.1	c.530C>A	p.Pro177His	missense_variant	5/10	ENST00000452892.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCM2L	ENST00000452892.3	c.530C>A	p.Pro177His	missense_variant	5/10	2	NM_001365692.1	P1
CCM2L	ENST00000262659.12	c.530C>A	p.Pro177His	missense_variant	5/9	1
	ENST00000662576.1	n.815+9922G>T		intron_variant, non_coding_transcript_variant
	ENST00000653258.1	n.704+9922G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.38e-7 AC: 1 AN: 1193226 Hom.: 0 Cov.: 31 AF XY: 0.00000172 AC XY: 1 AN XY: 582888

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: 0.00000101

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Mar 15, 2024

The c.530C>A (p.P177H) alteration is located in exon 5 (coding exon 5) of the CCM2L gene. This alteration results from a C to A substitution at nucleotide position 530, causing the proline (P) at amino acid position 177 to be replaced by a histidine (H). 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	0.092
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Uncertain	0.99
Eigen	Benign	0.050
Eigen_PC	Benign	-0.024
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.38	T
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.76	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-2.4	N
REVEL	Benign	0.10
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.11	T
Polyphen		0.90	P
Vest4		0.21
MutPred		0.18		Gain of solvent accessibility (P = 0.0281);
MVP		0.60
MPC		1.2
ClinPred		0.54	D
GERP RS		2.4
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-30606809;