19-46605832-C-G

Variant names:

• chr19-46605832-C-G
• rs1463101364
• NM_005184.4:c.9C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_005184.4(CALM3):​c.9C>G​(p.Asp3Glu) 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 benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D3D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CALM3 NM_005184.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.06
• 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• catecholaminergic polymorphic ventricular tachycardia

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a chain Calmodulin-3 (size 147) in uniprot entity CALM3_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_005184.4
• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.32430682).

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.9C>G	p.Asp3Glu	missense	Exon 2 of 6	NP_005175.2	P0DP25
	CALM3	NM_001329922.1		c.9C>G	p.Asp3Glu	missense	Exon 2 of 6	NP_001316851.1	P0DP23
	CALM3	NM_001329921.1		c.-100C>G		5_prime_UTR	Exon 2 of 6	NP_001316850.1	Q96HY3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALM3	ENST00000291295.14	TSL:1 MANE Select	c.9C>G	p.Asp3Glu	missense	Exon 2 of 6	ENSP00000291295.8	P0DP25
	CALM3	ENST00000599839.5	TSL:1	c.-100C>G		5_prime_UTR	Exon 3 of 7	ENSP00000471225.1	Q96HY3
	CALM3	ENST00000866718.1		c.9C>G	p.Asp3Glu	missense	Exon 2 of 6	ENSP00000536777.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000282 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
CardioboostArm	Benign	0.00050
BayesDel_addAF	Benign	0.00057	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Benign	0.94
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.019
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.1
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.12
Sift4G	Benign	0.52	T
Vest4		0.56
MutPred		0.25		Gain of loop (P = 0.1081)
MVP		0.85
MPC		1.4
ClinPred		0.37	T
GERP RS		3.3
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.47
gMVP		0.76
Mutation Taster		=56/43	polymorphism

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: rs1463101364; hg19: chr19-47109089;