14-90401385-A-T

Variant names:

• chr14-90401385-A-T
• rs267607276
• NM_006888.6:c.161A>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_006888.6(CALM1):​c.161A>T​(p.Asn54Ile) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CALM1 NM_006888.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:4 O:1
• Conservation: PhyloP100: 9.32

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• 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, catecholaminergic polymorphic ventricular tachycardia 4, long QT syndrome 14, catecholaminergic polymorphic ventricular tachycardia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936
• PP5: Variant 14-90401385-A-T is Pathogenic according to our data. Variant chr14-90401385-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39757.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALM1	NM_006888.6	c.161A>T	p.Asn54Ile	missense_variant	Exon 3 of 6	ENST00000356978.9	NP_008819.1
CALM1	NM_001363670.2	c.164A>T	p.Asn55Ile	missense_variant	Exon 3 of 6		NP_001350599.1
CALM1	NM_001363669.2	c.53A>T	p.Asn18Ile	missense_variant	Exon 3 of 6		NP_001350598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALM1	ENST00000356978.9	c.161A>T	p.Asn54Ile	missense_variant	Exon 3 of 6	1	NM_006888.6	ENSP00000349467.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 4 Pathogenic:3 Other:1

Oct 05, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 22, 2020

SIB Swiss Institute of Bioinformatics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as likely pathogenic for Ventricular tachycardia, catecholaminergic polymorphic, 4, 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); Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1 upgraded to moderate); Well-established functional studies show a deleterious effect (PS3 downgraded to moderate). -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jul 23, 2012

Nyegaard lab; Aarhus University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:1

May 05, 2014

Blueprint Genetics

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	28
DANN	Uncertain	0.98
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;.;D;.;.;.
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D
MetaSVM	Uncertain	0.22	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.7	D;D;D;.;D;D
REVEL	Pathogenic	0.89
Sift4G	Uncertain	0.036	D;D;D;D;D;D
Polyphen		0.76	.;.;P;.;.;.
Vest4		0.89, 0.86, 0.86, 0.89, 0.86
MVP		0.98
MPC		3.4
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.80
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs267607276; hg19: chr14-90867729;