1-160198578-G-A

Variant names:

• chr1-160198578-G-A
• rs822450
• NM_001231.5:c.829-99G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.57
• Publications: 12 publications found

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

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001231.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASQ1	NM_001231.5	MANE Select	c.829-99G>A		intron	N/A	NP_001222.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASQ1	ENST00000368078.8	TSL:1 MANE Select	c.829-99G>A		intron	N/A	ENSP00000357057.3
	CASQ1	ENST00000467691.1	TSL:3	c.-9-99G>A		intron	N/A	ENSP00000418051.1
	CASQ1	ENST00000481081.1	TSL:2	n.714-99G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.350 AC: 53164 AN: 151884 Hom.: 10760 Cov.: 31

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

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

GnomAD4 genome AF: 0.350 AC: 53171 AN: 152004 Hom.: 10756 Cov.: 31 AF XY: 0.353 AC XY: 26255 AN XY: 74292

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: 94 AN: 294

European-Non Finnish (NFE) AF: 0.434 AC: 29521 AN: 67958

Other (OTH) AF: 0.358 AC: 754 AN: 2108

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.4
DANN	Benign	0.51
PhyloP100		1.6
PromoterAI		-0.0034	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs822450; hg19: chr1-160168368;