rs199744595

Positions:

• chr14-90404693-C-A
• chr14-90404693-C-G
• chr14-90404693-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PS1_Very_Strong PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The ENST00000356978.9(CALM1):​c.426C>A​(p.Phe142Leu) variant causes a missense change. 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 Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Synonymous variant affecting the same amino acid position (i.e. F142F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CALM1 ENST00000356978.9 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.72

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PS1: Transcript ENST00000356978.9 (CALM1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 426161
• PM1: In a domain EF-hand 4 (size 32) in uniprot entity CALM1_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in ENST00000356978.9
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.896
• PP5: Variant 14-90404693-C-A is Pathogenic according to our data. Variant chr14-90404693-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 961658.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CALM1	NM_006888.6	c.426C>A	p.Phe142Leu	missense_variant	6/6	ENST00000356978.9	NP_008819.1
CALM1	NM_001363670.2	c.429C>A	p.Phe143Leu	missense_variant	6/6		NP_001350599.1
CALM1	NM_001363669.2	c.318C>A	p.Phe106Leu	missense_variant	6/6		NP_001350598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CALM1	ENST00000356978.9	c.426C>A	p.Phe142Leu	missense_variant	6/6	1	NM_006888.6	ENSP00000349467	P1
	ENST00000555853.1	n.44+499G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 4;C4015671:Long QT syndrome 14 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 02, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.73	.;T;.;.;.
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D
MetaSVM	Uncertain	-0.057	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.3	D;D;.;D;D
REVEL	Uncertain	0.56
Sift4G	Uncertain	0.019	D;D;D;D;D
Polyphen		0.95	.;P;.;.;.
Vest4		0.90
MutPred		0.66		.;Loss of catalytic residue at F143 (P = 0.0075);.;.;.;
MVP		0.98
MPC		2.5
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.26		Position offset: -4

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

Publications

LitVar

Other links and lift over

dbSNP: rs199744595; hg19: chr14-90871037;