20-32018092-C-G

Position:

• chr20-32018092-C-G

Variant summary

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

The NM_001365692.1(CCM2L):​c.396C>G​(p.Ile132Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,764 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CCM2L NM_001365692.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.315

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCM2L	NM_001365692.1	c.396C>G	p.Ile132Met	missense_variant	4/10	ENST00000452892.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCM2L	ENST00000452892.3	c.396C>G	p.Ile132Met	missense_variant	4/10	2	NM_001365692.1	P1
CCM2L	ENST00000262659.12	c.396C>G	p.Ile132Met	missense_variant	4/9	1
	ENST00000662576.1	n.816-10443G>C		intron_variant, non_coding_transcript_variant
	ENST00000653258.1	n.705-10443G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460764 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726698

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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 24, 2023

The c.396C>G (p.I132M) alteration is located in exon 4 (coding exon 4) of the CCM2L gene. This alteration results from a C to G substitution at nucleotide position 396, causing the isoleucine (I) at amino acid position 132 to be replaced by a methionine (M). 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	0.73
BayesDel_addAF	Benign	0.0075	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Benign	0.97
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	0.95	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.24
Sift	Benign	0.040	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.34		Gain of catalytic residue at I132 (P = 0.0053);
MVP		0.39
MPC		1.6
ClinPred		0.95	D
GERP RS		0.23
gMVP		0.75

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-30605895;