rs1555814427

Variant names:

• chr19-46609125-A-G
• rs1555814427
• NM_005184.4:c.422A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_005184.4(CALM3):​c.422A>G​(p.Glu141Gly) 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CALM3 NM_005184.4 missense, splice_region
• Scores: Splicing: ADA: 0.5428
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.32

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity CALM3_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935
• PP5: Variant 19-46609125-A-G is Pathogenic according to our data. Variant chr19-46609125-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 458198.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALM3	NM_005184.4	c.422A>G	p.Glu141Gly	missense_variant, splice_region_variant	Exon 6 of 6	ENST00000291295.14	NP_005175.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALM3	ENST00000291295.14	c.422A>G	p.Glu141Gly	missense_variant, splice_region_variant	Exon 6 of 6	1	NM_005184.4	ENSP00000291295.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome 1 Pathogenic:1

Sep 11, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed in individual(s) with long QT syndrome (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 458198). 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 and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. The CALM1, CALM2 and CALM3 genes code for three identical proteins of calmodulin that only differ in their promoter and untranslated regions (PMID: 11569915). The same variant c.422A>G (p.Glu141Gly) located in CALM1 has been shown to disrupt calcium binding in calmodulin and reported to occur de novo in an individual with long QT syndrome (PMID: 26969752). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with glycine at codon 141 of the CALM3 protein (p.Glu141Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	31
DANN	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	.;.;.;.;.;T;.
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.51	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.7	D;D;.;.;.;.;.
REVEL	Pathogenic	0.87
Sift4G	Uncertain	0.019	D;D;D;D;D;D;D
Vest4		0.91
MutPred		0.73		.;Loss of stability (P = 0.0439);.;.;.;.;Loss of stability (P = 0.0439);
MVP		0.96
MPC		3.0
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.86
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.54
dbscSNV1_RF	Benign	0.49
SpliceAI score (max)		0.020		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: rs1555814427; hg19: chr19-47112382;