rs1060502607

Positions:

• chr19-46608846-G-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_005184.4(CALM3):​c.286G>C​(p.Asp96His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CALM3 NM_005184.4 missense, splice_region
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.93

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 Pathogenic. Variant got 15 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity CALM2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CALM3. . Gene score misZ 2.9788 (greater than the threshold 3.09). Trascript score misZ 3.6287 (greater than threshold 3.09). GenCC has associacion of gene with long QT syndrome, familial long QT syndrome, long QT syndrome 16, catecholaminergic polymorphic ventricular tachycardia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893
• PP5: Variant 19-46608846-G-C is Pathogenic according to our data. Variant chr19-46608846-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 409870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CALM3	NM_005184.4	c.286G>C	p.Asp96His	missense_variant, splice_region_variant	5/6	ENST00000291295.14
LOC124904729	XR_007067276.1	n.223C>G		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CALM3	ENST00000291295.14	c.286G>C	p.Asp96His	missense_variant, splice_region_variant	5/6	1	NM_005184.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2018

This variant has been observed to be de novo in an individual with clinical features of CALM3-related disease (Invitae), and reported in the literature in an unrelated individual with long QT syndrome (PMID: 28491681). ClinVar contains an entry for this variant (Variation ID: 409870). For these reasons, this variant has been classified as Pathogenic. There are three different genes that encode calmodulin (CALM1, CALM2, and CALM3) that all have the same amino acid sequence, which suggests that changes in one version of the gene would have a similar effect on other versions of the gene (PMID: 26969752) A different missense substitution at this codon in CALM2 (p.Asp96Val) has been determined to be pathogenic (PMID: 23388215, 24563457, 24816216, 24958779). This suggests that the aspartic acid residue is critical for CALM3 protein function and that other missense substitutions affecting this residue may also be pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with histidine at codon 96 of the CALM3 protein (p.Asp96His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. It also falls at the first nucleotide of exon 5 of the CALM3 coding sequence. -

Long QT syndrome 16 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jul 17, 2023

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a likely mechanism of disease in this gene and is associated with long QT syndrome 16 (MIM# 618782). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). This variant is also a binding site within the EF-hand III domain pair (DECIPHER, PMID: 30574507). (SP) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.(Asp96Gly) variant has been identified in one individual with LQTS and classified as a VUS (PMID: 30847666). (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified once as pathogenic by a clinical diagnostic laboratory (ClinVar). This variant has also been reported in three young children with severe LQTS and/or fetal bradycardia including a female patient from Hong Kong who was internally confirmed to be de novo for the variant (PMIDs: 28491681, 30530868, 31535183). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1207 - Parental origin of the variant is unresolved. The variant is not maternally inherited (by segregation testing). However, the proband's father has not been tested for the variant and it is unclear if the variant is de novo or paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;.;.;.;D;.
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D
MetaSVM	Uncertain	0.41	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-6.3	.;D;.;.;.;.
REVEL	Pathogenic	0.68
Sift4G	Uncertain	0.0080	D;D;D;D;D;D
Vest4		0.82
MutPred		0.76		.;Gain of ubiquitination at K95 (P = 0.0577);.;.;.;Gain of ubiquitination at K95 (P = 0.0577);
MVP		0.95
MPC		3.1
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: -33

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060502607; hg19: chr19-47112103;