Genetic Variant NM_006888.6:c.*417T>C (chr14-90405134-T-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_006888.6(CALM1):c.*417T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 167,722 control chromosomes in the GnomAD database, including 2,198 homozygotes. 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: 𝑓 0.13 ( 2007 hom., cov: 33)

Exomes 𝑓: 0.12 ( 191 hom. )

Consequence

CALM1
NM_006888.6 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.40

Publications

29 publications found

Variant links:

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

CALM1 links:

ENSG00000258424 (HGNC:):

ENSG00000258424 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.26).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.582 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CALM1	NM_006888.6 link	c.*417T>C	3_prime_UTR_variant	Exon 6 of 6	ENST00000356978.9	NP_008819.1	P0DP23P0DP24P0DP25B4DJ51
CALM1	NM_001363670.2 link	c.*417T>C	3_prime_UTR_variant	Exon 6 of 6		NP_001350599.1
CALM1	NM_001363669.2 link	c.*417T>C	3_prime_UTR_variant	Exon 6 of 6		NP_001350598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALM1	ENST00000356978.9 link	c.*417T>C		3_prime_UTR_variant	Exon 6 of 6	1	NM_006888.6	ENSP00000349467.4		P0DP23

Frequencies

GnomAD3 genomes

AF:

0.130

AC:

19742

AN:

152116

Hom.:

2010

Cov.:

show subpopulations

Gnomad AFR

AF:

0.145

Gnomad AMI

AF:

0.253

Gnomad AMR

AF:

0.172

Gnomad ASJ

AF:

0.124

Gnomad EAS

AF:

0.600

Gnomad SAS

AF:

0.136

Gnomad FIN

AF:

0.0886

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0801

Gnomad OTH

AF:

0.119

GnomAD4 exome

AF:

0.115

AC:

1785

AN:

15488

Hom.:

191

Cov.:

AF XY:

0.114

AC XY:

915

AN XY:

8004

show subpopulations

African (AFR)

AF:

0.138

AC:

AN:

392

American (AMR)

AF:

0.179

AC:

136

AN:

760

Ashkenazi Jewish (ASJ)

AF:

0.119

AC:

AN:

454

East Asian (EAS)

AF:

0.549

AC:

436

AN:

794

South Asian (SAS)

AF:

0.118

AC:

115

AN:

976

European-Finnish (FIN)

AF:

0.0709

AC:

AN:

1016

Middle Eastern (MID)

AF:

0.0962

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0798

AC:

812

AN:

10176

Other (OTH)

AF:

0.116

AC:

101

AN:

868

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

145

217

290

362

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.130

AC:

19768

AN:

152234

Hom.:

2007

Cov.:

AF XY:

0.134

AC XY:

9989

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.146

AC:

6052

AN:

41526

American (AMR)

AF:

0.173

AC:

2638

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.124

AC:

429

AN:

3470

East Asian (EAS)

AF:

0.599

AC:

3103

AN:

5178

South Asian (SAS)

AF:

0.136

AC:

655

AN:

4820

European-Finnish (FIN)

AF:

0.0886

AC:

940

AN:

10612

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0801

AC:

5449

AN:

68016

Other (OTH)

AF:

0.119

AC:

252

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

801

1602

2403

3204

4005

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

208

416

624

832

1040

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0911

Hom.:

342

Bravo

AF:

0.140

Asia WGS

AF:

0.317

AC:

1101

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.92

PhyloP100

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over