14-90399936-A-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 publications found

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]

CALM1 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 14

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P
• catecholaminergic polymorphic ventricular tachycardia 4

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006888.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALM1	NM_006888.6	MANE Select	c.4-129A>G		intron	N/A	NP_008819.1	P0DP23
	CALM1	NM_001363670.2		c.7-129A>G		intron	N/A	NP_001350599.1
	CALM1	NM_001363669.2		c.-105-129A>G		intron	N/A	NP_001350598.1	Q96HY3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALM1	ENST00000356978.9	TSL:1 MANE Select	c.4-129A>G		intron	N/A	ENSP00000349467.4	P0DP23
	CALM1	ENST00000544280.6	TSL:1	c.-105-129A>G		intron	N/A	ENSP00000442853.2	Q96HY3
	CALM1	ENST00000553964.5	TSL:1	n.2005A>G		non_coding_transcript_exon	Exon 1 of 5

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

African (AFR) AF: 0.119 AC: 1635 AN: 13700

American (AMR) AF: 0.00895 AC: 247 AN: 27610

Ashkenazi Jewish (ASJ) AF: 0.000724 AC: 11 AN: 15202

East Asian (EAS) AF: 0.00 AC: 0 AN: 33662

South Asian (SAS) AF: 0.000297 AC: 15 AN: 50456

European-Finnish (FIN) AF: 0.00268 AC: 123 AN: 45902

Middle Eastern (MID) AF: 0.00449 AC: 11 AN: 2448

European-Non Finnish (NFE) AF: 0.00254 AC: 794 AN: 312490

Other (OTH) AF: 0.0107 AC: 305 AN: 28506

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

African (AFR) AF: 0.119 AC: 4960 AN: 41534

American (AMR) AF: 0.0135 AC: 206 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4834

European-Finnish (FIN) AF: 0.00310 AC: 33 AN: 10630

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00240 AC: 163 AN: 68038

Other (OTH) AF: 0.0223 AC: 47 AN: 2112

Alfa AF: 0.0180 Hom.: 45

Bravo AF: 0.0406

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.80
DANN	Benign	0.46
PhyloP100		0.081
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3729783; hg19: chr14-90866280;