chr20-32019006-C-A

Variant names:

• chr20-32019006-C-A
• rs1307319572
• NM_001365692.1:c.530C>A

Variant summary

Our verdict is Uncertain significance. The variant received 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. 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: 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
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30310905).

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.530C>A	p.Pro177His	missense	Exon 5 of 10	NP_001352621.1	Q9NUG4-1
	CCM2L	NM_080625.4		c.530C>A	p.Pro177His	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.530C>A	p.Pro177His	missense	Exon 5 of 10	ENSP00000392448.2	Q9NUG4-1
	CCM2L	ENST00000262659.12	TSL:1	c.530C>A	p.Pro177His	missense	Exon 5 of 9	ENSP00000262659.8	Q9NUG4-2
	CCM2L	ENST00000953124.1		c.530C>A	p.Pro177His	missense	Exon 5 of 10	ENSP00000623183.1

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23606

American (AMR) AF: 0.00 AC: 0 AN: 10056

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16762

East Asian (EAS) AF: 0.00 AC: 0 AN: 27036

South Asian (SAS) AF: 0.00 AC: 0 AN: 47938

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27964

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3288

European-Non Finnish (NFE) AF: 0.00000101 AC: 1 AN: 988188

Other (OTH) AF: 0.00 AC: 0 AN: 48388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

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	0.092
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
PhyloP100		2.2
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
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs1307319572; hg19: chr20-30606809;