rs199744595

Variant names:

• chr14-90404693-C-A
• rs199744595
• NM_006888.6:c.426C>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS1_Very_Strong PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_006888.6(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 the same amino acid substitution has been previously reported as Pathogenic in 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 NM_006888.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.72
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 14

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P
• catecholaminergic polymorphic ventricular tachycardia 4

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen

ENSG00000258424 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PS1: Transcript NM_006888.6 (CALM1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_006888.6
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the CALM1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 3.051 (below the threshold of 3.09). Trascript score misZ: 3.5833 (above the threshold of 3.09). GenCC associations: The gene is linked to catecholaminergic polymorphic ventricular tachycardia 4, catecholaminergic polymorphic ventricular tachycardia, long QT syndrome 14, long QT syndrome.
• 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 VariationId is 961658.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006888.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALM1	NM_006888.6	MANE Select	c.426C>A	p.Phe142Leu	missense	Exon 6 of 6	NP_008819.1
	CALM1	NM_001363670.2		c.429C>A	p.Phe143Leu	missense	Exon 6 of 6	NP_001350599.1
	CALM1	NM_001363669.2		c.318C>A	p.Phe106Leu	missense	Exon 6 of 6	NP_001350598.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALM1	ENST00000356978.9	TSL:1 MANE Select	c.426C>A	p.Phe142Leu	missense	Exon 6 of 6	ENSP00000349467.4
	CALM1	ENST00000544280.6	TSL:1	c.318C>A	p.Phe106Leu	missense	Exon 6 of 6	ENSP00000442853.2
	CALM1	ENST00000553964.5	TSL:1	n.2556C>A		non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Catecholaminergic polymorphic ventricular tachycardia 4;C4015671:Long QT syndrome 14 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostArm	Pathogenic	1.0
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
MetaSVM	Uncertain	-0.057	T
PhyloP100		4.7
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.56
Sift4G	Uncertain	0.019	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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs199744595; hg19: chr14-90871037;