Genetic Variant CASQ1:c.365-28C>T (chr1-160193719-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001231.5(CASQ1):c.365-28C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 1,292,934 control chromosomes in the GnomAD database, including 90,849 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. There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.31 ( 8667 hom., cov: 32)

Exomes 𝑓: 0.37 ( 82182 hom. )

Consequence

CASQ1
NM_001231.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.28

Publications

19 publications found

Variant links:

Genes affected

CASQ1 (HGNC:1512): (calsequestrin 1) This gene encodes the skeletal muscle specific member of the calsequestrin protein family. Calsequestrin functions as a luminal sarcoplasmic reticulum calcium sensor in both cardiac and skeletal muscle cells. This protein, also known as calmitine, functions as a calcium regulator in the mitochondria of skeletal muscle. This protein is absent in patients with Duchenne and Becker types of muscular dystrophy. [provided by RefSeq, Jun 2013]

CASQ1 Gene-Disease associations (from GenCC):

myopathy due to calsequestrin and SERCA1 protein overload
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
tubular aggregate myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CASQ1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.54 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASQ1	NM_001231.5 link	c.365-28C>T		intron_variant	Intron 2 of 10	ENST00000368078.8	NP_001222.3	P31415

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASQ1	ENST00000368078.8 link	c.365-28C>T		intron_variant	Intron 2 of 10	1	NM_001231.5	ENSP00000357057.3		P31415
CASQ1	ENST00000481081.1 link	n.250-28C>T		intron_variant	Intron 1 of 7	2

Frequencies

GnomAD3 genomes

AF:

0.309

AC:

46743

AN:

151186

Hom.:

8672

Cov.:

show subpopulations

Gnomad AFR

AF:

0.101

Gnomad AMI

AF:

0.354

Gnomad AMR

AF:

0.381

Gnomad ASJ

AF:

0.438

Gnomad EAS

AF:

0.558

Gnomad SAS

AF:

0.294

Gnomad FIN

AF:

0.395

Gnomad MID

AF:

0.326

Gnomad NFE

AF:

0.382

Gnomad OTH

AF:

0.315

GnomAD2 exomes

AF:

0.372

AC:

85948

AN:

230924

AF XY:

0.371

show subpopulations

Gnomad AFR exome

AF:

0.0928

Gnomad AMR exome

AF:

0.414

Gnomad ASJ exome

AF:

0.440

Gnomad EAS exome

AF:

0.558

Gnomad FIN exome

AF:

0.399

Gnomad NFE exome

AF:

0.380

Gnomad OTH exome

AF:

0.380

GnomAD4 exome

AF:

0.373

AC:

426299

AN:

1141628

Hom.:

82182

Cov.:

AF XY:

0.372

AC XY:

215240

AN XY:

578926

show subpopulations

African (AFR)

AF:

0.0887

AC:

2334

AN:

26316

American (AMR)

AF:

0.406

AC:

15936

AN:

39294

Ashkenazi Jewish (ASJ)

AF:

0.438

AC:

10280

AN:

23478

East Asian (EAS)

AF:

0.543

AC:

19614

AN:

36120

South Asian (SAS)

AF:

0.303

AC:

23615

AN:

77914

European-Finnish (FIN)

AF:

0.413

AC:

21656

AN:

52450

Middle Eastern (MID)

AF:

0.340

AC:

1622

AN:

4774

European-Non Finnish (NFE)

AF:

0.376

AC:

312979

AN:

832008

Other (OTH)

AF:

0.371

AC:

18263

AN:

49274

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

13061

26121

39182

52242

65303

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8776

17552

26328

35104

43880

<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:

0.309

AC:

46751

AN:

151306

Hom.:

8667

Cov.:

AF XY:

0.314

AC XY:

23251

AN XY:

73942

show subpopulations

African (AFR)

AF:

0.101

AC:

4157

AN:

41358

American (AMR)

AF:

0.380

AC:

5799

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.438

AC:

1516

AN:

3464

East Asian (EAS)

AF:

0.557

AC:

2875

AN:

5158

South Asian (SAS)

AF:

0.296

AC:

1423

AN:

4814

European-Finnish (FIN)

AF:

0.395

AC:

4137

AN:

10468

Middle Eastern (MID)

AF:

0.323

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.382

AC:

25760

AN:

67480

Other (OTH)

AF:

0.316

AC:

666

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1509

3019

4528

6038

7547

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

464

928

1392

1856

2320

<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:

0.350

Hom.:

26873

Bravo

AF:

0.296

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

3.3

(source)

DANN

Benign

0.51

PhyloP100

1.3

BranchPoint Hunter

2.0

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