19-46603377-G-A

Variant names:

• chr19-46603377-G-A
• rs4380146
• NM_005184.4:c.3+1940G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005184.4(CALM3):​c.3+1940G>A variant causes a intron 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CALM3 NM_005184.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.41
• Publications: 6 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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALM3	NM_005184.4	MANE Select	c.3+1940G>A		intron	N/A	NP_005175.2
	CALM3	NM_001329922.1		c.3+1167G>A		intron	N/A	NP_001316851.1
	CALM3	NM_001329921.1		c.-106+2201G>A		intron	N/A	NP_001316850.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALM3	ENST00000291295.14	TSL:1 MANE Select	c.3+1940G>A		intron	N/A	ENSP00000291295.8
	CALM3	ENST00000599839.5	TSL:1	c.-106+738G>A		intron	N/A	ENSP00000471225.1
	CALM3	ENST00000596362.1	TSL:2	c.3+1167G>A		intron	N/A	ENSP00000472141.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.9
DANN	Benign	0.93
PhyloP100		-3.4

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: rs4380146; hg19: chr19-47106634;