rs730882252

Positions:

• chr14-90404482-A-G

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_006888.6(CALM1):​c.389A>G​(p.Asp130Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D130V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CALM1 NM_006888.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.27

Genes affected

CALM1 (HGNC:1442): (calmodulin 1) This gene encodes one of three calmodulin proteins which are members of the EF-hand calcium-binding protein family. Calcium-induced activation of calmodulin regulates and modulates the function of cardiac ion channels. Two pseudogenes have been identified on chromosome 7 and X. Multiple transcript variants encoding different isoforms have been found for this gene.A missense mutation in the CALM1 gene has been associated with ventricular tachycardia.[provided by RefSeq, May 2020]

CALM1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity CALM2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CALM1. . Gene score misZ 3.051 (greater than the threshold 3.09). Trascript score misZ 3.5833 (greater than threshold 3.09). GenCC has associacion of gene with long QT syndrome, catecholaminergic polymorphic ventricular tachycardia 4, long QT syndrome 14, catecholaminergic polymorphic ventricular tachycardia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• PP5: Variant 14-90404482-A-G is Pathogenic according to our data. Variant chr14-90404482-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CALM1	NM_006888.6	c.389A>G	p.Asp130Gly	missense_variant	5/6	ENST00000356978.9	NP_008819.1
CALM1	NM_001363670.2	c.392A>G	p.Asp131Gly	missense_variant	5/6		NP_001350599.1
CALM1	NM_001363669.2	c.281A>G	p.Asp94Gly	missense_variant	5/6		NP_001350598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CALM1	ENST00000356978.9	c.389A>G	p.Asp130Gly	missense_variant	5/6	1	NM_006888.6	ENSP00000349467.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 14 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 05, 2013	- -
Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Jul 22, 2020	This variant is interpreted as pathogenic for Long QT syndrome 14, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3); Assumed de novo, but no confirmation of paternity and maternity (PM6); Well-established functional studies show a deleterious effect (PS3); Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation (PM1). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Nov 19, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;.;D;.;.;.
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-4.5	D;D;D;.;D;D
REVEL	Pathogenic	0.94
Sift4G	Uncertain	0.014	D;D;D;D;D;D
Polyphen		0.98	.;.;D;.;.;.
Vest4		0.96, 0.99, 0.89, 0.96, 0.98
MutPred		0.77		.;.;Loss of stability (P = 0.0086);.;.;.;
MVP		0.99
MPC		3.7
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs730882252; hg19: chr14-90870826;