rs35617141

Variant names:

• chr19-46608950-C-G
• rs35617141
• NM_005184.4:c.390C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-46608950-C-G
• chr19-46608950-C-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_005184.4(CALM3):​c.390C>G​(p.Asp130Glu) variant causes a missense change involving the alteration of a non-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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D130G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CALM3 NM_005184.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.64
• Publications: 0 publications found

Genes affected

CALM3 (HGNC:1449): (calmodulin 3) This gene encodes a member of a family of proteins that binds calcium and functions as a enzymatic co-factor. Activity of this protein is important in the regulation of the cell cycle and cytokinesis. Multiple alternatively spliced transcript variants have been observed at this gene. [provided by RefSeq, Aug 2016]

CALM3 Gene-Disease associations (from GenCC):

• familial long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 16

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

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen, G2P

LOC124904729 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_005184.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-46608949-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 812676.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 8 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.9788 (below the threshold of 3.09). Trascript score misZ: 3.6287 (above the threshold of 3.09). GenCC associations: The gene is linked to long QT syndrome, long QT syndrome 16, familial long QT syndrome, catecholaminergic polymorphic ventricular tachycardia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89
• PP5: Variant 19-46608950-C-G is Pathogenic according to our data. Variant chr19-46608950-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1358003.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005184.4. 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
	CALM3	NM_005184.4	MANE Select	c.390C>G	p.Asp130Glu	missense	Exon 5 of 6	NP_005175.2
	CALM3	NM_001329922.1		c.390C>G	p.Asp130Glu	missense	Exon 5 of 6	NP_001316851.1
	CALM3	NM_001329921.1		c.282C>G	p.Asp94Glu	missense	Exon 5 of 6	NP_001316850.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALM3	ENST00000291295.14	TSL:1 MANE Select	c.390C>G	p.Asp130Glu	missense	Exon 5 of 6	ENSP00000291295.8
	CALM3	ENST00000599839.5	TSL:1	c.282C>G	p.Asp94Glu	missense	Exon 6 of 7	ENSP00000471225.1
	CALM3	ENST00000866718.1		c.426C>G	p.Asp142Glu	missense	Exon 5 of 6	ENSP00000536777.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Long QT syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostArm	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.32	D
PhyloP100		2.6
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.72
Sift4G	Uncertain	0.020	D
Vest4		0.86
MutPred		0.77		Loss of stability (P = 0.0518)
MVP		0.99
MPC		2.6
ClinPred		0.98	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75
gMVP		0.99
Mutation Taster		=46/54	disease causing

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

Other links and lift over

dbSNP: rs35617141; hg19: chr19-47112207;