14-90401385-A-G

Variant names:

• chr14-90401385-A-G
• rs267607276
• NM_006888.6:c.161A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_006888.6(CALM1):​c.161A>G​(p.Asn54Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,258 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N54I) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: CALM1 NM_006888.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32
• Publications: 5 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a chain Calmodulin-1 (size 147) in uniprot entity CALM1_HUMAN there are 18 pathogenic changes around while only 0 benign (100%) in NM_006888.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-90401385-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 39757.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the CALM1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 3.051 (below the threshold of 3.09). Trascript score misZ: 3.5833 (above the threshold of 3.09). GenCC associations: The gene is linked to long QT syndrome 14, catecholaminergic polymorphic ventricular tachycardia, catecholaminergic polymorphic ventricular tachycardia 4, long QT syndrome.

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.161A>G	p.Asn54Ser	missense	Exon 3 of 6	NP_008819.1	P0DP23
	CALM1	NM_001363670.2		c.164A>G	p.Asn55Ser	missense	Exon 3 of 6	NP_001350599.1
	CALM1	NM_001363669.2		c.53A>G	p.Asn18Ser	missense	Exon 3 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.161A>G	p.Asn54Ser	missense	Exon 3 of 6	ENSP00000349467.4	P0DP23
	CALM1	ENST00000544280.6	TSL:1	c.53A>G	p.Asn18Ser	missense	Exon 3 of 6	ENSP00000442853.2	Q96HY3
	CALM1	ENST00000553964.5	TSL:1	n.2291A>G		non_coding_transcript_exon	Exon 2 of 5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152258 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74394

African (AFR) AF: 0.0000241 AC: 1 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
CardioboostArm	Benign	0.00055
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	26
DANN	Benign	0.94
Eigen	Benign	-0.020
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.57	T
PhyloP100		9.3
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.37
Sift4G	Benign	0.30	T
Polyphen		0.0030	B
Vest4		0.61
MutPred		0.43		Gain of phosphorylation at N55 (P = 0.0434)
MVP		0.83
MPC		1.4
ClinPred		0.97	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.67
gMVP		0.87
Mutation Taster		=87/13	polymorphism

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: rs267607276; hg19: chr14-90867729;