rs1555814427

Variant names:

• chr19-46609125-A-G
• rs1555814427
• NM_005184.4:c.422A>G

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.422A>G​(p.Glu141Gly) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E141K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CALM3 NM_005184.4 missense, splice_region
• Scores: Splicing: ADA: 0.5428
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.32
• Publications: 1 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

LOC124904729 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-46608981-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 812678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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, 0.935
• PP5: Variant 19-46609125-A-G is Pathogenic according to our data. Variant chr19-46609125-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 458198.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.422A>G	p.Glu141Gly	missense splice_region	Exon 6 of 6	NP_005175.2	P0DP25
	CALM3	NM_001329922.1		c.422A>G	p.Glu141Gly	missense splice_region	Exon 6 of 6	NP_001316851.1	P0DP23
	CALM3	NM_001329921.1		c.314A>G	p.Glu105Gly	missense splice_region	Exon 6 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.422A>G	p.Glu141Gly	missense splice_region	Exon 6 of 6	ENSP00000291295.8	P0DP25
	CALM3	ENST00000599839.5	TSL:1	c.314A>G	p.Glu105Gly	missense splice_region	Exon 7 of 7	ENSP00000471225.1	Q96HY3
	CALM3	ENST00000866718.1		c.458A>G	p.Glu153Gly	missense splice_region	Exon 6 of 6	ENSP00000536777.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely 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	0.83
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	31
DANN	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.51	D
PhyloP100		9.3
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.87
Sift4G	Uncertain	0.019	D
Vest4		0.91
MutPred		0.73		Loss of stability (P = 0.0439)
MVP		0.96
MPC		3.0
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.86
gMVP		0.97
Mutation Taster		=27/73	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.54
dbscSNV1_RF	Benign	0.49
SpliceAI score (max)		0.020		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: rs1555814427; hg19: chr19-47112382;