rs149634686

Positions:

• chr19-16495819-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_145046.5(CALR3):​c.125A>G​(p.Asn42Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000231 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: CALR3 NM_145046.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.72

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005948633).
• BP6: Variant 19-16495819-T-C is Benign according to our data. Variant chr19-16495819-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 241949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-16495819-T-C is described in Lovd as [Benign]. Variant chr19-16495819-T-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 170 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CALR3	NM_145046.5	c.125A>G	p.Asn42Ser	missense_variant	2/9	ENST00000269881.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CALR3	ENST00000269881.8	c.125A>G	p.Asn42Ser	missense_variant	2/9	1	NM_145046.5	P1
CALR3	ENST00000600762.1	c.116A>G	p.Asn39Ser	missense_variant	2/4	3

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 170 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00394

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.000350 AC: 88 AN: 251468 Hom.: 0 AF XY: 0.000191 AC XY: 26 AN XY: 135920

Gnomad AFR exome AF: 0.00498

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000139 AC: 203 AN: 1461864 Hom.: 0 Cov.: 31 AF XY: 0.000116 AC XY: 84 AN XY: 727232

Gnomad4 AFR exome AF: 0.00496

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.00112 AC: 170 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.00109 AC XY: 81 AN XY: 74418

Gnomad4 AFR AF: 0.00392

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000950

Alfa AF: 0.000249 Hom.: 0

Bravo AF: 0.00129

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000420 AC: 51

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy 19 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Sep 08, 2016	- -
Likely 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	Invitae	Jan 18, 2024	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 26, 2024	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

CALR3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 24, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

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

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.099
Eigen_PC	Benign	0.079
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.47	N
MutationTaster	Benign	0.98	N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.11
Sift	Benign	0.54	T
Sift4G	Benign	0.38	T
Polyphen		0.48	P
Vest4		0.23
MVP		0.44
MPC		0.56
ClinPred		0.16	T
GERP RS		4.4
Varity_R		0.15
gMVP		0.21

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: rs149634686; hg19: chr19-16606630;