20-32018092-C-G

Variant names:

• chr20-32018092-C-G
• rs2064756046
• NM_001365692.1:c.396C>G

Variant summary

Our verdict is Uncertain significance. The variant received 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. 14/21 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
• Publications: 0 publications found

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]

ENSG00000226239 (HGNC:58356):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365692.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCM2L	NM_001365692.1	MANE Select	c.396C>G	p.Ile132Met	missense	Exon 4 of 10	NP_001352621.1	Q9NUG4-1
	CCM2L	NM_080625.4		c.396C>G	p.Ile132Met	missense	Exon 4 of 9	NP_542192.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCM2L	ENST00000452892.3	TSL:2 MANE Select	c.396C>G	p.Ile132Met	missense	Exon 4 of 10	ENSP00000392448.2	Q9NUG4-1
	CCM2L	ENST00000262659.12	TSL:1	c.396C>G	p.Ile132Met	missense	Exon 4 of 9	ENSP00000262659.8	Q9NUG4-2
	CCM2L	ENST00000953124.1		c.396C>G	p.Ile132Met	missense	Exon 4 of 10	ENSP00000623183.1

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

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53002

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5438

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111876

Other (OTH) AF: 0.00 AC: 0 AN: 60320

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-0.32
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
Mutation Taster		=58/42	polymorphism

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: rs2064756046; hg19: chr20-30605895;