chr1-160195976-A-G

Position:

• chr1-160195976-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The ENST00000368078.8(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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). 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 ENST00000368078.8 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 4.88

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• 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 id is 183021.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-160195976-A-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.19782728). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASQ1	NM_001231.5	c.731A>G	p.Asp244Gly	missense_variant	6/11	ENST00000368078.8	NP_001222.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASQ1	ENST00000368078.8	c.731A>G	p.Asp244Gly	missense_variant	6/11	1	NM_001231.5	ENSP00000357057	P1
CASQ1	ENST00000481081.1	n.616A>G		non_coding_transcript_exon_variant	5/8	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Myopathy due to calsequestrin and SERCA1 protein overload Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2014	- -
Likely pathogenic, no assertion criteria provided	provider interpretation	Solve-RD Consortium	Jun 01, 2022	Variant confirmed as disease-causing by referring clinical team -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 20, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CASQ1 function (PMID: 25116801, 26416891). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 183021). This missense change has been observed in individuals with CASQ1-related myopathy (PMID: 25116801). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 244 of the CASQ1 protein (p.Asp244Gly). -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	0.99	D;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs730882052; hg19: chr1-160165766; COSMIC: COSV100927361; COSMIC: COSV100927361;