rs730882052

Variant names:

• chr1-160195976-A-G
• rs730882052
• NM_001231.5:c.731A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PS3 PM2 PP5_Moderate BP4

The NM_001231.5(CASQ1):​c.731A>G​(p.Asp244Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV002239126: Experimental studies have shown that this missense change affects CASQ1 function (PMID:25116801, 26416891).". Synonymous variant affecting the same amino acid position (i.e. D244D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CASQ1 NM_001231.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 4.88
• 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: Orphanet, Labcorp Genetics (formerly Invitae)
• tubular aggregate myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002239126: Experimental studies have shown that this missense change affects CASQ1 function (PMID: 25116801, 26416891).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-160195976-A-G is Pathogenic according to our data. Variant chr1-160195976-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 183021.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19782728). . Strength limited to SUPPORTING due to the PP5.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASQ1	NM_001231.5	MANE Select	c.731A>G	p.Asp244Gly	missense	Exon 6 of 11	NP_001222.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASQ1	ENST00000368078.8	TSL:1 MANE Select	c.731A>G	p.Asp244Gly	missense	Exon 6 of 11	ENSP00000357057.3	P31415
	CASQ1	ENST00000954562.1		c.731A>G	p.Asp244Gly	missense	Exon 7 of 12	ENSP00000624621.1
	CASQ1	ENST00000954563.1		c.731A>G	p.Asp244Gly	missense	Exon 6 of 9	ENSP00000624622.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Myopathy due to calsequestrin and SERCA1 protein overload (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Benign	0.75
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.025	N
PhyloP100		4.9
PrimateAI	Benign	0.48	T
PROVEAN	Benign	1.0	N
REVEL	Pathogenic	0.71
Sift	Benign	0.88	T
Sift4G	Benign	0.77	T
Polyphen		0.0	B
Vest4		0.31
MutPred		0.36		Gain of glycosylation at P246 (P = 0.1078)
MVP		0.69
MPC		0.16
ClinPred		0.48	T
GERP RS		4.8
Varity_R		0.52
gMVP		0.75
Mutation Taster		=20/80	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs730882052; hg19: chr1-160165766; COSMIC: COSV100927361; COSMIC: COSV100927361;