rs3729761

Positions:

• chr19-46608486-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_005184.4(CALM3):​c.183C>T​(p.Asn61=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000767 in 1,613,490 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (1 hom.)
• Consequence: CALM3 NM_005184.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.28

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]

LOC124904729 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 19-46608486-C-T is Benign according to our data. Variant chr19-46608486-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 240116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46608486-C-T is described in Lovd as [Benign]. Variant chr19-46608486-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.28 with no splicing effect.
• BS2: High AC in GnomAd4 at 63 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CALM3	NM_005184.4	c.183C>T	p.Asn61=	synonymous_variant	4/6	ENST00000291295.14
LOC124904729	XR_007067276.1	n.583G>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CALM3	ENST00000291295.14	c.183C>T	p.Asn61=	synonymous_variant	4/6	1	NM_005184.4	P1

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000537 AC: 135 AN: 251462 Hom.: 0 AF XY: 0.000574 AC XY: 78 AN XY: 135904

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.000751

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000826

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000803 AC: 1174 AN: 1461200 Hom.: 1 Cov.: 31 AF XY: 0.000795 AC XY: 578 AN XY: 726936

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000870

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000948

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74454

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000794

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000736 Hom.: 0

Bravo AF: 0.000472

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000533

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2020	This variant is associated with the following publications: (PMID: 26350513) -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 28, 2023	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Long QT syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 28, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.44
DANN	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs3729761; hg19: chr19-47111743;