rs191723671

Positions:

• chr14-90400055-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_006888.6(CALM1):​c.4-10C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000264 in 1,606,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: CALM1 NM_006888.6 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0009739
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.22

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 14-90400055-C-G is Benign according to our data. Variant chr14-90400055-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 389903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-90400055-C-G is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 225 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CALM1	NM_006888.6	c.4-10C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000356978.9
CALM1	NM_001363669.2	c.-105-10C>G		splice_polypyrimidine_tract_variant, intron_variant
CALM1	NM_001363670.2	c.7-10C>G		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CALM1	ENST00000356978.9	c.4-10C>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_006888.6	P1

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 223 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00510

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

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: 0.0000147

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000323 AC: 81 AN: 250540 Hom.: 0 AF XY: 0.000281 AC XY: 38 AN XY: 135398

Gnomad AFR exome AF: 0.00456

Gnomad AMR exome AF: 0.000146

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: 0.000327

GnomAD4 exome AF: 0.000137 AC: 199 AN: 1454208 Hom.: 0 Cov.: 27 AF XY: 0.000116 AC XY: 84 AN XY: 724046

Gnomad4 AFR exome AF: 0.00505

Gnomad4 AMR exome AF: 0.000314

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.000216

GnomAD4 genome AF: 0.00148 AC: 225 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.00137 AC XY: 102 AN XY: 74432

Gnomad4 AFR AF: 0.00513

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00125 Hom.: 0

Bravo AF: 0.00171

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 31, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 20, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00097
dbscSNV1_RF	Benign	0.046
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: rs191723671; hg19: chr14-90866399;