14-90400062-T-C

Position:

• chr14-90400062-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_006888.6(CALM1):​c.4-3T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000618 in 1,457,462 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CALM1 NM_006888.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00008803
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.45

Genes affected

CALM1 (HGNC:1442): (calmodulin 1) This gene encodes one of three calmodulin proteins which are members of the EF-hand calcium-binding protein family. Calcium-induced activation of calmodulin regulates and modulates the function of cardiac ion channels. Two pseudogenes have been identified on chromosome 7 and X. Multiple transcript variants encoding different isoforms have been found for this gene.A missense mutation in the CALM1 gene has been associated with ventricular tachycardia.[provided by RefSeq, May 2020]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CALM1	NM_006888.6	c.4-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000356978.9
CALM1	NM_001363669.2	c.-105-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
CALM1	NM_001363670.2	c.7-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CALM1	ENST00000356978.9	c.4-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006888.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251116 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135710

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.00000618 AC: 9 AN: 1457462 Hom.: 0 Cov.: 28 AF XY: 0.00000551 AC XY: 4 AN XY: 725426

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 4;C4015671:Long QT syndrome 14 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 24, 2023

This sequence change falls in intron 1 of the CALM1 gene. It does not directly change the encoded amino acid sequence of the CALM1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs754359981, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CALM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1740325). 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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 31, 2018

The c.4-3T>C intronic variant results from a T to C substitution 3 nucleotides upstream from coding exon 2 in the CALM1 gene. This nucleotide position is not well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is not predicted to have any significant effect on this splice acceptor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	14
DANN	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000088
dbscSNV1_RF	Benign	0.016
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: rs754359981; hg19: chr14-90866406;