19-12938659-T-C

Position:

• chr19-12938659-T-C

Variant summary

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

The NM_004343.4(CALR):​c.-21T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,593,522 control chromosomes in the GnomAD database, including 1,484 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (772 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (712 hom.)
• Consequence: CALR NM_004343.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.267

Genes affected

CALR (HGNC:1455): (calreticulin) Calreticulin is a highly conserved chaperone protein which resides primarily in the endoplasmic reticulum, and is involved in a variety of cellular processes, among them, cell adhesion. Additionally, it functions in protein folding quality control and calcium homeostasis. Calreticulin is also found in the nucleus, suggesting that it may have a role in transcription regulation. Systemic lupus erythematosus is associated with increased autoantibody titers against calreticulin. Recurrent mutations in calreticulin have been linked to various neoplasms, including the myeloproliferative type.[provided by RefSeq, May 2020]

CALR (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 19-12938659-T-C is Benign according to our data. Variant chr19-12938659-T-C is described in ClinVar as [Benign]. Clinvar id is 1290353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CALR	NM_004343.4	c.-21T>C		5_prime_UTR_premature_start_codon_gain_variant	1/9	ENST00000316448.10	NP_004334.1
CALR	NM_004343.4	c.-21T>C		5_prime_UTR_variant	1/9	ENST00000316448.10	NP_004334.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CALR	ENST00000316448	c.-21T>C		5_prime_UTR_premature_start_codon_gain_variant	1/9	1	NM_004343.4	ENSP00000320866.4
CALR	ENST00000316448	c.-21T>C		5_prime_UTR_variant	1/9	1	NM_004343.4	ENSP00000320866.4

Frequencies

GnomAD3 genomes AF: 0.0537 AC: 8167 AN: 152158 Hom.: 767 Cov.: 32

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0166

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0363

GnomAD3 exomes AF: 0.0122 AC: 2682 AN: 219052 Hom.: 237 AF XY: 0.00926 AC XY: 1121 AN XY: 121024

Gnomad AFR exome AF: 0.191

Gnomad AMR exome AF: 0.00814

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000699

Gnomad FIN exome AF: 0.0000529

Gnomad NFE exome AF: 0.000344

Gnomad OTH exome AF: 0.00518

GnomAD4 exome AF: 0.00549 AC: 7912 AN: 1441246 Hom.: 712 Cov.: 30 AF XY: 0.00468 AC XY: 3357 AN XY: 716598

Gnomad4 AFR exome AF: 0.198

Gnomad4 AMR exome AF: 0.00968

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000258

Gnomad4 SAS exome AF: 0.000225

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000200

Gnomad4 OTH exome AF: 0.0120

GnomAD4 genome AF: 0.0538 AC: 8187 AN: 152276 Hom.: 772 Cov.: 32 AF XY: 0.0522 AC XY: 3889 AN XY: 74468

Gnomad4 AFR AF: 0.189

Gnomad4 AMR AF: 0.0165

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.0360

Alfa AF: 0.0264 Hom.: 67

Bravo AF: 0.0605

Asia WGS AF: 0.0140 AC: 49 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	14
DANN	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs11547567; hg19: chr19-13049473;