rs2275703

Variant names:

• chr1-160195305-A-C
• rs2275703
• NM_001231.5:c.578-156A>C

Variant summary

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

The NM_001231.5(CASQ1):​c.578-156A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.384 in 151,768 control chromosomes in the GnomAD database, including 12,533 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 0.38 (12533 hom., cov: 30)
• Consequence: CASQ1 NM_001231.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.09
• Publications: 17 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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.481 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASQ1	NM_001231.5	c.578-156A>C		intron_variant	Intron 4 of 10	ENST00000368078.8	NP_001222.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASQ1	ENST00000368078.8	c.578-156A>C		intron_variant	Intron 4 of 10	1	NM_001231.5	ENSP00000357057.3
CASQ1	ENST00000481081.1	n.463-156A>C		intron_variant	Intron 3 of 7	2

Frequencies

GnomAD3 genomes AF: 0.384 AC: 58183 AN: 151650 Hom.: 12529 Cov.: 30

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.568

Gnomad AMR AF: 0.422

Gnomad ASJ AF: 0.432

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.400

Gnomad FIN AF: 0.449

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.486

Gnomad OTH AF: 0.419

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.384 AC: 58213 AN: 151768 Hom.: 12533 Cov.: 30 AF XY: 0.380 AC XY: 28183 AN XY: 74136

African (AFR) AF: 0.196 AC: 8104 AN: 41380

American (AMR) AF: 0.422 AC: 6446 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.432 AC: 1500 AN: 3472

East Asian (EAS) AF: 0.201 AC: 1032 AN: 5144

South Asian (SAS) AF: 0.399 AC: 1907 AN: 4780

European-Finnish (FIN) AF: 0.449 AC: 4725 AN: 10518

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.486 AC: 32969 AN: 67896

Other (OTH) AF: 0.423 AC: 894 AN: 2114

Alfa AF: 0.426 Hom.: 5318

Bravo AF: 0.378

Asia WGS AF: 0.296 AC: 1031 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.58
DANN	Benign	0.63
PhyloP100		-1.1
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: rs2275703; hg19: chr1-160165095; COSMIC: COSV63624486; COSMIC: COSV63624486;