chr14-90404386-A-G

Variant names:

• chr14-90404386-A-G
• rs267607277
• NM_006888.6:c.293A>G

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PM2 PP2 PP5_Very_Strong

The NM_006888.6(CALM1):​c.293A>G​(p.Asn98Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000655574: Experimental studies have shown that this missense change affects CALM1 function (PMID:23040497, 24563457, 24816216, 25557436, 26309258)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N98I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CALM1 NM_006888.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 9.27
• Publications: 6 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• catecholaminergic polymorphic ventricular tachycardia

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

ENSG00000258424 (HGNC:):

ACMG classification

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

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000655574: Experimental studies have shown that this missense change affects CALM1 function (PMID: 23040497, 24563457, 24816216, 25557436, 26309258).; SCV000845664: Functional studies have demonstrated the variant has an impact on protein structure/function (Hwang et al. Circ Res. 2014 Mar 28;114(7):1114-24; Søndergaard et al. FEBS J. 2015 Feb;282(4):803-16; Søndergaard et al. J Biol Chem. 2015 Oct 23;290(43):26151-62; Vassilakopoulou et al. Biochim Biophys Acta. 2015 Nov;1850(11):2168-76).; SCV002747815: Functional studies in various experimental systems have shown that this alteration would attenuate calcium binding (Nyegaard M et al. Am. J. Hum. Genet., 2012 Oct;91:703-12; Hwang HS et al. Circ. Res., 2014 Mar;114:1114-24; Limpitikul WB et al. J. Mol. Cell. Cardiol., 2014 Sep;74:115-24; Søndergaard MT et al. FEBS J., 2015 Feb;282:803-16; Søndergaard MT et al. J. Biol. Chem., 2015 Oct;290:26151-62; Yu CC et al. Heart Rhythm, 2016 Aug;13:1716-23; Vassilakopoulou V et al. Biochim. Biophys. Acta, 2015 Nov;1850:2168-76).; SCV005360611: Functional studies demonstrated this variant significantly prolonged calmodulin action potentials (Limpitikul et al. 2014. PubMed ID: 24816216) and a transgenic mouse model recapitulated the human cardiac phenotype (Tsai et al. 2020. PubMed ID: 32929985).
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 long QT syndrome 14, catecholaminergic polymorphic ventricular tachycardia, catecholaminergic polymorphic ventricular tachycardia 4, long QT syndrome.
• PP5: Variant 14-90404386-A-G is Pathogenic according to our data. Variant chr14-90404386-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 39758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALM1	NM_006888.6	MANE Select	c.293A>G	p.Asn98Ser	missense	Exon 5 of 6	NP_008819.1	P0DP23
	CALM1	NM_001363670.2		c.296A>G	p.Asn99Ser	missense	Exon 5 of 6	NP_001350599.1
	CALM1	NM_001363669.2		c.185A>G	p.Asn62Ser	missense	Exon 5 of 6	NP_001350598.1	Q96HY3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALM1	ENST00000356978.9	TSL:1 MANE Select	c.293A>G	p.Asn98Ser	missense	Exon 5 of 6	ENSP00000349467.4	P0DP23
	CALM1	ENST00000544280.6	TSL:1	c.185A>G	p.Asn62Ser	missense	Exon 5 of 6	ENSP00000442853.2	Q96HY3
	CALM1	ENST00000553964.5	TSL:1	n.2423A>G		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Catecholaminergic polymorphic ventricular tachycardia 4 (5)
1	-	-	CALM1-related disorder (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Catecholaminergic polymorphic ventricular tachycardia (1)
1	-	-	Catecholaminergic polymorphic ventricular tachycardia 1 (1)
1	-	-	Catecholaminergic polymorphic ventricular tachycardia 4;C4015671:Long QT syndrome 14 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	27
DANN	Benign	0.92
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.53	T
PhyloP100		9.3
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.44
Sift4G	Benign	0.20	T
Polyphen		0.032	B
Vest4		0.79
MutPred		0.64		Gain of glycosylation at N99 (P = 0.0445)
MVP		0.83
MPC		1.6
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.79
gMVP		0.89
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs267607277; hg19: chr14-90870730;