19-46603377-G-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005184.4(CALM3):​c.3+1940G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.771 in 152,226 control chromosomes in the GnomAD database, including 46,096 homozygotes. 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: 𝑓 0.77 (46096 hom., 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.927 is higher than 0.05.

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>T		intron	N/A	NP_005175.2
	CALM3	NM_001329922.1		c.3+1167G>T		intron	N/A	NP_001316851.1
	CALM3	NM_001329921.1		c.-106+2201G>T		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>T		intron	N/A	ENSP00000291295.8
	CALM3	ENST00000599839.5	TSL:1	c.-106+738G>T		intron	N/A	ENSP00000471225.1
	CALM3	ENST00000596362.1	TSL:2	c.3+1167G>T		intron	N/A	ENSP00000472141.1

Frequencies

GnomAD3 genomes AF: 0.771 AC: 117206 AN: 152108 Hom.: 46037 Cov.: 33

Gnomad AFR AF: 0.908

Gnomad AMI AF: 0.595

Gnomad AMR AF: 0.785

Gnomad ASJ AF: 0.805

Gnomad EAS AF: 0.950

Gnomad SAS AF: 0.811

Gnomad FIN AF: 0.673

Gnomad MID AF: 0.813

Gnomad NFE AF: 0.683

Gnomad OTH AF: 0.765

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

GnomAD4 genome AF: 0.771 AC: 117326 AN: 152226 Hom.: 46096 Cov.: 33 AF XY: 0.774 AC XY: 57599 AN XY: 74410

African (AFR) AF: 0.908 AC: 37762 AN: 41570

American (AMR) AF: 0.785 AC: 12001 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.805 AC: 2795 AN: 3472

East Asian (EAS) AF: 0.949 AC: 4916 AN: 5178

South Asian (SAS) AF: 0.812 AC: 3920 AN: 4828

European-Finnish (FIN) AF: 0.673 AC: 7110 AN: 10570

Middle Eastern (MID) AF: 0.823 AC: 242 AN: 294

European-Non Finnish (NFE) AF: 0.683 AC: 46418 AN: 68004

Other (OTH) AF: 0.768 AC: 1621 AN: 2112

Alfa AF: 0.725 Hom.: 113751

Bravo AF: 0.785

Asia WGS AF: 0.892 AC: 3101 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.4
DANN	Benign	0.84
PhyloP100		-3.4
Mutation Taster		=100/0	polymorphism (auto)

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;