Genetic Variant NM_001231.5:c.829-99G>A (chr1-160198578-G-A) – 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.829-99G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.403 in 812,808 control chromosomes in the GnomAD database, including 70,132 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 0.35 ( 10756 hom., cov: 31)

Exomes 𝑓: 0.42 ( 59376 hom. )

Consequence

CASQ1
NM_001231.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.57

Publications

12 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

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASQ1	NM_001231.5 link	c.829-99G>A		intron_variant	Intron 7 of 10	ENST00000368078.8	NP_001222.3	P31415

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CASQ1	ENST00000368078.8 link	c.829-99G>A	intron_variant	Intron 7 of 10	1	NM_001231.5	ENSP00000357057.3	P31415
CASQ1	ENST00000467691.1 link	c.-9-99G>A	intron_variant	Intron 1 of 4	3		ENSP00000418051.1	C9JAC8
CASQ1	ENST00000481081.1 link	n.714-99G>A	intron_variant	Intron 6 of 7	2

Frequencies

GnomAD3 genomes

AF:

0.350

AC:

53164

AN:

151884

Hom.:

10760

Cov.:

show subpopulations

Gnomad AFR

AF:

0.135

Gnomad AMI

AF:

0.343

Gnomad AMR

AF:

0.421

Gnomad ASJ

AF:

0.483

Gnomad EAS

AF:

0.530

Gnomad SAS

AF:

0.288

Gnomad FIN

AF:

0.442

Gnomad MID

AF:

0.329

Gnomad NFE

AF:

0.434

Gnomad OTH

AF:

0.358

GnomAD4 exome

AF:

0.416

AC:

274659

AN:

660804

Hom.:

59376

AF XY:

0.411

AC XY:

142133

AN XY:

346136

show subpopulations

African (AFR)

AF:

0.133

AC:

2253

AN:

16882

American (AMR)

AF:

0.426

AC:

12044

AN:

28278

Ashkenazi Jewish (ASJ)

AF:

0.475

AC:

8023

AN:

16908

East Asian (EAS)

AF:

0.517

AC:

18210

AN:

35210

South Asian (SAS)

AF:

0.290

AC:

16634

AN:

57392

European-Finnish (FIN)

AF:

0.467

AC:

23240

AN:

49776

Middle Eastern (MID)

AF:

0.359

AC:

1443

AN:

4014

European-Non Finnish (NFE)

AF:

0.427

AC:

179204

AN:

419212

Other (OTH)

AF:

0.411

AC:

13608

AN:

33132

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

7573

15147

22720

30294

37867

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2798

5596

8394

11192

13990

<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:

0.350

AC:

53171

AN:

152004

Hom.:

10756

Cov.:

AF XY:

0.353

AC XY:

26255

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.135

AC:

5598

AN:

41474

American (AMR)

AF:

0.421

AC:

6427

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.483

AC:

1675

AN:

3468

East Asian (EAS)

AF:

0.530

AC:

2732

AN:

5152

South Asian (SAS)

AF:

0.290

AC:

1395

AN:

4808

European-Finnish (FIN)

AF:

0.442

AC:

4662

AN:

10554

Middle Eastern (MID)

AF:

0.320

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.434

AC:

29521

AN:

67958

Other (OTH)

AF:

0.358

AC:

754

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1656

3312

4968

6624

8280

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

512

1024

1536

2048

2560

<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:

0.360

Hom.:

3326

Bravo

AF:

0.339

Asia WGS

AF:

0.366

AC:

1273

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

9.4

(source)

DANN

Benign

0.51

PhyloP100

1.6

PromoterAI

-0.0034

Neutral

(source)

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