20-32019048-C-T

Variant names:

• chr20-32019048-C-T
• rs2064772012
• NM_001365692.1:c.572C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001365692.1(CCM2L):​c.572C>T​(p.Thr191Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,149,604 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T191P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CCM2L NM_001365692.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.47
• 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 0 ACMG points.

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.572C>T	p.Thr191Ile	missense	Exon 5 of 10	NP_001352621.1	Q9NUG4-1
	CCM2L	NM_080625.4		c.572C>T	p.Thr191Ile	missense	Exon 5 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.572C>T	p.Thr191Ile	missense	Exon 5 of 10	ENSP00000392448.2	Q9NUG4-1
	CCM2L	ENST00000262659.12	TSL:1	c.572C>T	p.Thr191Ile	missense	Exon 5 of 9	ENSP00000262659.8	Q9NUG4-2
	CCM2L	ENST00000953124.1		c.572C>T	p.Thr191Ile	missense	Exon 5 of 10	ENSP00000623183.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 151446 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000217 AC: 25 AN: 1149604 Hom.: 0 Cov.: 31 AF XY: 0.0000287 AC XY: 16 AN XY: 557010

African (AFR) AF: 0.00 AC: 0 AN: 22736

American (AMR) AF: 0.00 AC: 0 AN: 8154

Ashkenazi Jewish (ASJ) AF: 0.0000680 AC: 1 AN: 14714

East Asian (EAS) AF: 0.00 AC: 0 AN: 25736

South Asian (SAS) AF: 0.000509 AC: 20 AN: 39264

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25754

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3058

European-Non Finnish (NFE) AF: 0.00000207 AC: 2 AN: 964132

Other (OTH) AF: 0.0000434 AC: 2 AN: 46056

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 151446 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 73928

African (AFR) AF: 0.00 AC: 0 AN: 41336

American (AMR) AF: 0.00 AC: 0 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67760

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	Benign	0.25
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Uncertain	0.98
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.43	T
M_CAP	Pathogenic	0.76	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.97	L
PhyloP100		3.5
PrimateAI	Pathogenic	0.97	D
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.18
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.23	T
Polyphen		0.99	D
Vest4		0.36
MutPred		0.22		Loss of phosphorylation at T191 (P = 0.0092)
MVP		0.48
MPC		1.4
ClinPred		0.81	D
GERP RS		1.4
gMVP		0.29
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2064772012; hg19: chr20-30606851;