19-16482548-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_145046.5(CALR3):c.820G>A(p.Val274Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,614,166 control chromosomes in the GnomAD database, including 1,058 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (140 hom., cov: 33)
  • Exomes 𝑓: 0.011 (918 hom.)
• Consequence: CALR3 NM_145046.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.36

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030251443).
• BP6: Variant 19-16482548-C-T is Benign according to our data. Variant chr19-16482548-C-T is described in ClinVar as [Benign]. Clinvar id is 192183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-16482548-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0804 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CALR3	NM_145046.5	c.820G>A	p.Val274Ile	missense_variant	7/9	ENST00000269881.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CALR3	ENST00000269881.8	c.820G>A	p.Val274Ile	missense_variant	7/9	1	NM_145046.5	P1
CALR3	ENST00000602234.1	n.494G>A		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.0267 AC: 4065 AN: 152168 Hom.: 136 Cov.: 33

Gnomad AFR AF: 0.0528

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0835

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.0302

Gnomad SAS AF: 0.00725

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00429

Gnomad OTH AF: 0.0272

GnomAD3 exomes AF: 0.0347 AC: 8722 AN: 251488 Hom.: 752 AF XY: 0.0264 AC XY: 3586 AN XY: 135922

Gnomad AFR exome AF: 0.0514

Gnomad AMR exome AF: 0.189

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.0246

Gnomad SAS exome AF: 0.00503

Gnomad FIN exome AF: 0.00365

Gnomad NFE exome AF: 0.00429

Gnomad OTH exome AF: 0.0248

GnomAD4 exome AF: 0.0110 AC: 16047 AN: 1461880 Hom.: 918 Cov.: 46 AF XY: 0.00986 AC XY: 7174 AN XY: 727244

Gnomad4 AFR exome AF: 0.0534

Gnomad4 AMR exome AF: 0.175

Gnomad4 ASJ exome AF: 0.00425

Gnomad4 EAS exome AF: 0.0237

Gnomad4 SAS exome AF: 0.00512

Gnomad4 FIN exome AF: 0.00399

Gnomad4 NFE exome AF: 0.00351

Gnomad4 OTH exome AF: 0.0129

GnomAD4 genome AF: 0.0269 AC: 4089 AN: 152286 Hom.: 140 Cov.: 33 AF XY: 0.0274 AC XY: 2041 AN XY: 74462

Gnomad4 AFR AF: 0.0530

Gnomad4 AMR AF: 0.0842

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.0305

Gnomad4 SAS AF: 0.00684

Gnomad4 FIN AF: 0.00377

Gnomad4 NFE AF: 0.00429

Gnomad4 OTH AF: 0.0269

Alfa AF: 0.00985 Hom.: 115

Bravo AF: 0.0368

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.0497 AC: 219

ESP6500EA AF: 0.00593 AC: 51

ExAC AF: 0.0301 AC: 3657

Asia WGS AF: 0.0280 AC: 97 AN: 3478

EpiCase AF: 0.00338

EpiControl AF: 0.00362

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hypertrophic cardiomyopathy 19 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 03, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 17, 2017	Variant summary: The CALR3 c.820G>A (p.Val274Ile) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict benign outcome for this variant. This variant was found in 3671/123152 control chromosomes (320 homozygotes) from ExAC and literature, predominantly observed in the Latino subpopulation at a frequency of 0.214458 (2483/11578). This frequency is about 8578 times the estimated maximal expected allele frequency of a pathogenic CALR3 variant (0.000025), thus this is a common benign polymorphism found primarily in the populations of Latino origin. In addition, multiple clinical diagnostic laboratories/reputable databases in ClinVar have classified this variant as benign. To our knowledge, this variant has not been reported in affected individuals in literature. Taken together, this variant is classified as benign. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2012

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.019
Dann	Benign	0.75
DEOGEN2	Benign	0.070	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.52	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.035
Sift	Benign	0.23	T
Sift4G	Benign	0.23	T
Polyphen		0.0090	B
Vest4		0.029
MPC		0.12
ClinPred		0.00074	T
GERP RS		-3.0
Varity_R		0.024
gMVP		0.082

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: rs12459238; hg19: chr19-16593359;