chr14-90404396-C-T

Variant names:

• chr14-90404396-C-T
• rs143503733
• NM_006888.6:c.303C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_006888.6(CALM1):​c.303C>T​(p.Ile101Ile) variant causes a synonymous change. The variant allele was found at a frequency of 0.00106 in 1,613,656 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: CALM1 NM_006888.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.14
• Publications: 1 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

ENSG00000258424 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 14-90404396-C-T is Benign according to our data. Variant chr14-90404396-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 67 AD gene.

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.303C>T	p.Ile101Ile	synonymous	Exon 5 of 6	NP_008819.1	P0DP23
	CALM1	NM_001363670.2		c.306C>T	p.Ile102Ile	synonymous	Exon 5 of 6	NP_001350599.1
	CALM1	NM_001363669.2		c.195C>T	p.Ile65Ile	synonymous	Exon 5 of 6	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.303C>T	p.Ile101Ile	synonymous	Exon 5 of 6	ENSP00000349467.4	P0DP23
	CALM1	ENST00000544280.6	TSL:1	c.195C>T	p.Ile65Ile	synonymous	Exon 5 of 6	ENSP00000442853.2	Q96HY3
	CALM1	ENST00000553964.5	TSL:1	n.2433C>T		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000809

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000805 AC: 202 AN: 251016 AF XY: 0.000774

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00166

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00112 AC: 1642 AN: 1461368 Hom.: 2 Cov.: 30 AF XY: 0.00107 AC XY: 776 AN XY: 726998

African (AFR) AF: 0.000299 AC: 10 AN: 33456

American (AMR) AF: 0.0000672 AC: 3 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.000356 AC: 19 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00141 AC: 1567 AN: 1111756

Other (OTH) AF: 0.000712 AC: 43 AN: 60372

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152288 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74460

African (AFR) AF: 0.000217 AC: 9 AN: 41568

American (AMR) AF: 0.000131 AC: 2 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000809 AC: 55 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000898 Hom.: 0

Bravo AF: 0.000416

EpiCase AF: 0.000764

EpiControl AF: 0.00119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	CALM1-related disorder (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 4;C4015671:Long QT syndrome 14 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Uncertain	1.0
PhyloP100		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs143503733; hg19: chr14-90870740;