19-46609881-A-G

Variant names:

• chr19-46609881-A-G
• rs10405893
• NM_005184.4:c.*728A>G

Variant summary

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

The NM_005184.4(CALM3):​c.*728A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.921 in 152,844 control chromosomes in the GnomAD database, including 64,862 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.92 (64572 hom., cov: 31)
  • Exomes 𝑓: 0.91 (290 hom.)
• Consequence: CALM3 NM_005184.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.618
• Publications: 14 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

ENSG00000269292 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.951 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALM3	NM_005184.4	MANE Select	c.*728A>G		3_prime_UTR	Exon 6 of 6	NP_005175.2	P0DP25
	CALM3	NM_001329922.1		c.*728A>G		3_prime_UTR	Exon 6 of 6	NP_001316851.1	P0DP23
	CALM3	NM_001329921.1		c.*728A>G		3_prime_UTR	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.*728A>G		3_prime_UTR	Exon 6 of 6	ENSP00000291295.8	P0DP25
	CALM3	ENST00000599839.5	TSL:1	c.*728A>G		3_prime_UTR	Exon 7 of 7	ENSP00000471225.1	Q96HY3
	CALM3	ENST00000866718.1		c.*728A>G		3_prime_UTR	Exon 6 of 6	ENSP00000536777.1

Frequencies

GnomAD3 genomes AF: 0.921 AC: 139986 AN: 152026 Hom.: 64513 Cov.: 31

Gnomad AFR AF: 0.957

Gnomad AMI AF: 0.879

Gnomad AMR AF: 0.934

Gnomad ASJ AF: 0.934

Gnomad EAS AF: 0.974

Gnomad SAS AF: 0.960

Gnomad FIN AF: 0.900

Gnomad MID AF: 0.921

Gnomad NFE AF: 0.892

Gnomad OTH AF: 0.913

GnomAD4 exome AF: 0.914 AC: 640 AN: 700 Hom.: 290 Cov.: 0 AF XY: 0.931 AC XY: 432 AN XY: 464

African (AFR) AF: 0.833 AC: 5 AN: 6

American (AMR) AF: 1.00 AC: 4 AN: 4

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 4 AN: 4

East Asian (EAS) AF: 1.00 AC: 4 AN: 4

South Asian (SAS) AF: 0.955 AC: 21 AN: 22

European-Finnish (FIN) AF: 0.907 AC: 401 AN: 442

Middle Eastern (MID) AF: 1.00 AC: 2 AN: 2

European-Non Finnish (NFE) AF: 0.921 AC: 186 AN: 202

Other (OTH) AF: 0.929 AC: 13 AN: 14

GnomAD4 genome AF: 0.921 AC: 140104 AN: 152144 Hom.: 64572 Cov.: 31 AF XY: 0.923 AC XY: 68623 AN XY: 74380

African (AFR) AF: 0.957 AC: 39716 AN: 41504

American (AMR) AF: 0.934 AC: 14279 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.934 AC: 3244 AN: 3472

East Asian (EAS) AF: 0.974 AC: 5016 AN: 5150

South Asian (SAS) AF: 0.960 AC: 4634 AN: 4826

European-Finnish (FIN) AF: 0.900 AC: 9521 AN: 10582

Middle Eastern (MID) AF: 0.918 AC: 270 AN: 294

European-Non Finnish (NFE) AF: 0.892 AC: 60689 AN: 68010

Other (OTH) AF: 0.914 AC: 1933 AN: 2114

Alfa AF: 0.909 Hom.: 91992

Bravo AF: 0.925

Asia WGS AF: 0.977 AC: 3396 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	2.9
DANN	Benign	0.78
PhyloP100		-0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs10405893; hg19: chr19-47113138; COSMIC: COSV52193990; COSMIC: COSV52193990;