19-16479219-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_145046.5(CALR3):c.1067G>T(p.Arg356Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,614,080 control chromosomes in the GnomAD database, including 28 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R356C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0071 ( 13 hom., cov: 31)

Exomes 𝑓: 0.00071 ( 15 hom. )

Consequence

CALR3
NM_145046.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.0740

Publications

5 publications found

Variant links:

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]

CALR3 Gene-Disease associations (from GenCC):

hypertrophic cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

CALR3 links:

ENSG00000141979 (HGNC:):

ENSG00000141979 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0045229197).

BP6

Variant 19-16479219-C-A is Benign according to our data. Variant chr19-16479219-C-A is described in ClinVar as Benign. ClinVar VariationId is 416237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00712 (1083/152196) while in subpopulation AFR AF = 0.0246 (1020/41540). AF 95% confidence interval is 0.0233. There are 13 homozygotes in GnomAd4. There are 487 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 1083 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145046.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALR3	NM_145046.5	MANE Select	c.1067G>T	p.Arg356Leu	missense	Exon 9 of 9	NP_659483.2	A0A140VJF7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CALR3	ENST00000269881.8	TSL:1 MANE Select	c.1067G>T	p.Arg356Leu	missense	Exon 9 of 9	ENSP00000269881.3	Q96L12
ENSG00000141979	ENST00000409035.1	TSL:2	n.*870G>T		non_coding_transcript_exon	Exon 12 of 12	ENSP00000386951.2	B8ZZF3
ENSG00000141979	ENST00000409035.1	TSL:2	n.*870G>T		3_prime_UTR	Exon 12 of 12	ENSP00000386951.2	B8ZZF3

Frequencies

GnomAD3 genomes

AF:

0.00711

AC:

1081

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00282

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:

0.000147

Gnomad OTH

AF:

0.00481

GnomAD2 exomes

AF:

0.00176

AC:

443

AN:

251474

AF XY:

0.00147

show subpopulations

Gnomad AFR exome

AF:

0.0231

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000791

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000711

AC:

1039

AN:

1461884

Hom.:

Cov.:

AF XY:

0.000635

AC XY:

462

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0235

AC:

786

AN:

33480

American (AMR)

AF:

0.00152

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000513

AC:

AN:

1112002

Other (OTH)

AF:

0.00192

AC:

116

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

133

199

266

332

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00712

AC:

1083

AN:

152196

Hom.:

Cov.:

AF XY:

0.00655

AC XY:

487

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.0246

AC:

1020

AN:

41540

American (AMR)

AF:

0.00282

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68024

Other (OTH)

AF:

0.00476

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

148

198

247

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00238

Hom.:

Bravo

AF:

0.00818

ESP6500AA

AF:

0.0238

AC:

105

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00221

AC:

268

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypertrophic cardiomyopathy 19 (2)

not provided (2)

not specified (2)

Cardiovascular phenotype (1)

Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0045

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

PhyloP100

-0.074

PrimateAI

Benign

0.23

PROVEAN

Uncertain

-3.7

REVEL

Benign

0.055

Sift

Uncertain

0.016

Sift4G

Uncertain

0.032

Polyphen

0.36

Vest4

0.34

MVP

0.30

MPC

0.31

ClinPred

0.021

GERP RS

-1.5

Varity_R

0.15

gMVP

0.68

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over