19-16496070-G-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_145046.5(CALR3):c.60C>G(p.Thr20=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000487 in 1,604,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00049 (0 hom.)
• Consequence: CALR3 NM_145046.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.467

Genes affected

CALR3 (HGNC:20407): (calreticulin 3) The protein encoded by this gene belongs to the calreticulin family, members of which are calcium-binding chaperones localized mainly in the endoplasmic reticulum. This protein is also localized to the endoplasmic reticulum lumen, however, its capacity for calcium-binding may be absent or much lower than other family members. This gene is specifically expressed in the testis, and may be required for sperm fertility. Mutation in this gene has been associated with familial hypertrophic cardiomyopathy. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 19-16496070-G-C is Benign according to our data. Variant chr19-16496070-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 416238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-16496070-G-C is described in Lovd as [Benign]. Variant chr19-16496070-G-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.467 with no splicing effect.
• BS2: High AC in GnomAd at 72 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CALR3	NM_145046.5	c.60C>G	p.Thr20=	synonymous_variant	1/9	ENST00000269881.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CALR3	ENST00000269881.8	c.60C>G	p.Thr20=	synonymous_variant	1/9	1	NM_145046.5	P1
CALR3	ENST00000600762.1	c.51C>G	p.Thr17=	synonymous_variant	1/4	3

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000436 AC: 102 AN: 233940 Hom.: 0 AF XY: 0.000559 AC XY: 71 AN XY: 126944

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000332

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000104

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000802

Gnomad OTH exome AF: 0.000694

GnomAD4 exome AF: 0.000489 AC: 710 AN: 1452658 Hom.: 0 Cov.: 31 AF XY: 0.000513 AC XY: 370 AN XY: 721788

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.000413

Gnomad4 ASJ exome AF: 0.0000388

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000472

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.000582

Gnomad4 OTH exome AF: 0.000533

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152264 Hom.: 0 Cov.: 33 AF XY: 0.000430 AC XY: 32 AN XY: 74462

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000779

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000402 Hom.: 0

Bravo AF: 0.000506

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy 19 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

-

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2012

This alteration is classified as likely benign based on a combination of the following: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	4.9
Dann	Benign	0.81

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: rs370721650; hg19: chr19-16606881;