14-90397248-G-C

Variant names:

• chr14-90397248-G-C
• rs1453073963
• NM_006888.6:c.3+15G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006888.6(CALM1):​c.3+15G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: CALM1 NM_006888.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.535
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).

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.3+15G>C		intron	N/A	NP_008819.1	P0DP23
	CALM1	NM_001363669.2		c.-106+590G>C		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.3+15G>C		intron	N/A	ENSP00000349467.4	P0DP23
	CALM1	ENST00000971957.1		c.3+15G>C		intron	N/A	ENSP00000642016.1
	CALM1	ENST00000447653.8	TSL:2	c.-203+15G>C		intron	N/A	ENSP00000403491.4	Q96HY3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399460 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 690360

African (AFR) AF: 0.00 AC: 0 AN: 31582

American (AMR) AF: 0.00 AC: 0 AN: 35682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25170

East Asian (EAS) AF: 0.00 AC: 0 AN: 35736

South Asian (SAS) AF: 0.00 AC: 0 AN: 79186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078960

Other (OTH) AF: 0.00 AC: 0 AN: 58034

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	17
DANN	Benign	0.79
PhyloP100		0.54
PromoterAI		-0.053	Neutral

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: rs1453073963; hg19: chr14-90863592;