1-160190778-C-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001231.5(CASQ1):c.27C>A(p.Pro9=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 1,614,068 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (14 hom.)
• Consequence: CASQ1 NM_001231.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.09

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 1-160190778-C-A is Benign according to our data. Variant chr1-160190778-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 716832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.09 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0076 (1157/152246) while in subpopulation AFR AF= 0.0256 (1064/41526). AF 95% confidence interval is 0.0243. There are 15 homozygotes in gnomad4. There are 545 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1154 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASQ1	NM_001231.5	c.27C>A	p.Pro9=	synonymous_variant	1/11	ENST00000368078.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASQ1	ENST00000368078.8	c.27C>A	p.Pro9=	synonymous_variant	1/11	1	NM_001231.5	P1

Frequencies

GnomAD3 genomes AF: 0.00759 AC: 1154 AN: 152128 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00221 AC: 555 AN: 251016 Hom.: 8 AF XY: 0.00169 AC XY: 229 AN XY: 135674

Gnomad AFR exome AF: 0.0254

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.00528

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000930 AC: 1360 AN: 1461822 Hom.: 14 Cov.: 31 AF XY: 0.000835 AC XY: 607 AN XY: 727214

Gnomad4 AFR exome AF: 0.0249

Gnomad4 AMR exome AF: 0.00190

Gnomad4 ASJ exome AF: 0.00436

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000148

Gnomad4 OTH exome AF: 0.00199

GnomAD4 genome AF: 0.00760 AC: 1157 AN: 152246 Hom.: 15 Cov.: 32 AF XY: 0.00732 AC XY: 545 AN XY: 74444

Gnomad4 AFR AF: 0.0256

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00370 Hom.: 2

Bravo AF: 0.00857

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
Cadd	Benign	11
Dann	Benign	0.86

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

LitVar

Other links and lift over

dbSNP: rs76394704; hg19: chr1-160160568;