NM_006888.6:c.4-129A>G

Variant names:

• chr14-90399936-A-G
• rs3729783
• NM_006888.6:c.4-129A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006888.6(CALM1):​c.4-129A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 682,298 control chromosomes in the GnomAD database, including 422 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (326 hom., cov: 33)
  • Exomes 𝑓: 0.0059 (96 hom.)
• Consequence: CALM1 NM_006888.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0810

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 14-90399936-A-G is Benign according to our data. Variant chr14-90399936-A-G is described in ClinVar as [Benign]. Clinvar id is 676355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALM1	NM_006888.6	c.4-129A>G		intron_variant	Intron 1 of 5	ENST00000356978.9	NP_008819.1
CALM1	NM_001363670.2	c.7-129A>G		intron_variant	Intron 1 of 5		NP_001350599.1
CALM1	NM_001363669.2	c.-105-129A>G		intron_variant	Intron 1 of 5		NP_001350598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALM1	ENST00000356978.9	c.4-129A>G		intron_variant	Intron 1 of 5	1	NM_006888.6	ENSP00000349467.4

Frequencies

GnomAD3 genomes AF: 0.0354 AC: 5387 AN: 152204 Hom.: 325 Cov.: 33

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0135

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00310

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00240

Gnomad OTH AF: 0.0225

GnomAD4 exome AF: 0.00593 AC: 3141 AN: 529976 Hom.: 96 Cov.: 6 AF XY: 0.00503 AC XY: 1436 AN XY: 285586

Gnomad4 AFR exome AF: 0.119

Gnomad4 AMR exome AF: 0.00895

Gnomad4 ASJ exome AF: 0.000724

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000297

Gnomad4 FIN exome AF: 0.00268

Gnomad4 NFE exome AF: 0.00254

Gnomad4 OTH exome AF: 0.0107

GnomAD4 genome AF: 0.0356 AC: 5419 AN: 152322 Hom.: 326 Cov.: 33 AF XY: 0.0344 AC XY: 2563 AN XY: 74498

Gnomad4 AFR AF: 0.119

Gnomad4 AMR AF: 0.0135

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00310

Gnomad4 NFE AF: 0.00240

Gnomad4 OTH AF: 0.0223

Alfa AF: 0.0179 Hom.: 23

Bravo AF: 0.0406

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.80
DANN	Benign	0.46

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs3729783; hg19: chr14-90866280;