Genetic Variant CALM1:c.-106+201G>T (chr14-90396859-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001363669.2(CALM1):c.-106+201G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 192,668 control chromosomes in the GnomAD database, including 6,433 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 5026 hom., cov: 33)

Exomes 𝑓: 0.25 ( 1407 hom. )

Consequence

CALM1
NM_001363669.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.18

Publications

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

CALM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 14-90396859-G-T is Benign according to our data. Variant chr14-90396859-G-T is described in ClinVar as Benign. ClinVar VariationId is 683288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363669.2. 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_001363669.2		c.-106+201G>T		intron	N/A	NP_001350598.1	Q96HY3
	CALM1	NM_006888.6	MANE Select	c.-372G>T		upstream_gene	N/A	NP_008819.1	P0DP23

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CALM1	ENST00000557020.5	TSL:4	c.-106+201G>T	intron	N/A	ENSP00000451062.1	G3V361
CALM1	ENST00000356978.9	TSL:1 MANE Select	c.-372G>T	upstream_gene	N/A	ENSP00000349467.4	P0DP23
CALM1	ENST00000971957.1		c.-372G>T	upstream_gene	N/A	ENSP00000642016.1

Frequencies

GnomAD3 genomes

AF:

0.254

AC:

38615

AN:

151928

Hom.:

5024

Cov.:

show subpopulations

Gnomad AFR

AF:

0.291

Gnomad AMI

AF:

0.216

Gnomad AMR

AF:

0.255

Gnomad ASJ

AF:

0.246

Gnomad EAS

AF:

0.0335

Gnomad SAS

AF:

0.252

Gnomad FIN

AF:

0.240

Gnomad MID

AF:

0.290

Gnomad NFE

AF:

0.252

Gnomad OTH

AF:

0.246

GnomAD4 exome

AF:

0.251

AC:

10202

AN:

40630

Hom.:

1407

AF XY:

0.254

AC XY:

5390

AN XY:

21244

show subpopulations

African (AFR)

AF:

0.288

AC:

392

AN:

1362

American (AMR)

AF:

0.276

AC:

287

AN:

1038

Ashkenazi Jewish (ASJ)

AF:

0.293

AC:

426

AN:

1456

East Asian (EAS)

AF:

0.0245

AC:

AN:

2412

South Asian (SAS)

AF:

0.294

AC:

133

AN:

452

European-Finnish (FIN)

AF:

0.263

AC:

942

AN:

3580

Middle Eastern (MID)

AF:

0.286

AC:

AN:

220

European-Non Finnish (NFE)

AF:

0.263

AC:

7170

AN:

27218

Other (OTH)

AF:

0.252

AC:

730

AN:

2892

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.524

Heterozygous variant carriers

371

742

1113

1484

1855

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.254

AC:

38639

AN:

152038

Hom.:

5026

Cov.:

AF XY:

0.251

AC XY:

18654

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.291

AC:

12075

AN:

41508

American (AMR)

AF:

0.255

AC:

3903

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.246

AC:

852

AN:

3466

East Asian (EAS)

AF:

0.0338

AC:

175

AN:

5176

South Asian (SAS)

AF:

0.250

AC:

1207

AN:

4820

European-Finnish (FIN)

AF:

0.240

AC:

2537

AN:

10554

Middle Eastern (MID)

AF:

0.281

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.252

AC:

17090

AN:

67904

Other (OTH)

AF:

0.247

AC:

521

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1490

2981

4471

5962

7452

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

402

804

1206

1608

2010

<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:

0.142

Hom.:

272

Bravo

AF:

0.255

Asia WGS

AF:

0.179

AC:

622

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

0.044

(source)

DANN

Benign

0.42

PhyloP100

-1.2

PromoterAI

0.11

Neutral

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over