rs373529765

Variant names:

• chr19-46608985-A-G
• rs373529765
• NM_005184.4:c.421+4A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-46608985-A-G
• chr19-46608985-A-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_005184.4(CALM3):​c.421+4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000344 in 1,600,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: CALM3 NM_005184.4 splice_region, intron
• Scores: Splicing: ADA: 0.2322
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.0880
• Publications: 0 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

LOC124904729 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 19-46608985-A-G is Benign according to our data. Variant chr19-46608985-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 409869. Variant chr19-46608985-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 409869. Variant chr19-46608985-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 409869. Variant chr19-46608985-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 409869. Variant chr19-46608985-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 409869. Variant chr19-46608985-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 409869. Variant chr19-46608985-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 409869. Variant chr19-46608985-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 409869. Variant chr19-46608985-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 409869. Variant chr19-46608985-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 409869. Variant chr19-46608985-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 409869. Variant chr19-46608985-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 409869. Variant chr19-46608985-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 409869. Variant chr19-46608985-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 409869. Variant chr19-46608985-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 409869. Variant chr19-46608985-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 409869. Variant chr19-46608985-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 409869. Variant chr19-46608985-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 409869. Variant chr19-46608985-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 409869. Variant chr19-46608985-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 409869.
• BS2: High AC in GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALM3	NM_005184.4	c.421+4A>G		splice_region_variant, intron_variant	Intron 5 of 5	ENST00000291295.14	NP_005175.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALM3	ENST00000291295.14	c.421+4A>G		splice_region_variant, intron_variant	Intron 5 of 5	1	NM_005184.4	ENSP00000291295.8

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000375 AC: 9 AN: 239782 AF XY: 0.0000309

Gnomad AFR exome AF: 0.000557

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000207 AC: 30 AN: 1448014 Hom.: 0 Cov.: 32 AF XY: 0.0000125 AC XY: 9 AN XY: 718984

African (AFR) AF: 0.000844 AC: 28 AN: 33184

American (AMR) AF: 0.00 AC: 0 AN: 43010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39500

South Asian (SAS) AF: 0.00 AC: 0 AN: 84438

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52974

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104340

Other (OTH) AF: 0.0000335 AC: 2 AN: 59770

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74428

African (AFR) AF: 0.000578 AC: 24 AN: 41542

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.000166

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome 1 Uncertain:1

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 5 of the CALM3 gene. It does not directly change the encoded amino acid sequence of the CALM3 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs373529765, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with CALM3-related conditions. ClinVar contains an entry for this variant (Variation ID: 409869). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Long QT syndrome 16 Uncertain:1

Apr 15, 2022

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Jul 03, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.69
CADD	Benign	21
DANN	Benign	0.73
PhyloP100		0.088

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.23
dbscSNV1_RF	Benign	0.37
SpliceAI score (max)		0.13		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: rs373529765; hg19: chr19-47112242;