19-12938601-C-T

Position:

• chr19-12938601-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The ENST00000587486.6(CALR):​n.24C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00452 in 1,110,162 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0045 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (64 hom.)
• Consequence: CALR ENST00000587486.6 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.432

Genes affected

CALR (HGNC:):

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 19-12938601-C-T is Benign according to our data. Variant chr19-12938601-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2501571.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00454 (692/152356) while in subpopulation EAS AF= 0.0318 (165/5192). AF 95% confidence interval is 0.0278. There are 4 homozygotes in gnomad4. There are 368 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.12938601C>T		intergenic_region
CALR	NM_004343.4	c.-79C>T		upstream_gene_variant		ENST00000316448.10	NP_004334.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CALR	ENST00000316448.10	c.-79C>T		upstream_gene_variant		1	NM_004343.4	ENSP00000320866.4

Frequencies

GnomAD3 genomes AF: 0.00455 AC: 692 AN: 152238 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0135

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.0315

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.00772

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00235

Gnomad OTH AF: 0.00334

GnomAD4 exome AF: 0.00452 AC: 4325 AN: 957806 Hom.: 64 Cov.: 13 AF XY: 0.00448 AC XY: 2188 AN XY: 488534

Gnomad4 AFR exome AF: 0.000741

Gnomad4 AMR exome AF: 0.0252

Gnomad4 ASJ exome AF: 0.00394

Gnomad4 EAS exome AF: 0.0349

Gnomad4 SAS exome AF: 0.00381

Gnomad4 FIN exome AF: 0.0106

Gnomad4 NFE exome AF: 0.00179

Gnomad4 OTH exome AF: 0.00461

GnomAD4 genome AF: 0.00454 AC: 692 AN: 152356 Hom.: 4 Cov.: 32 AF XY: 0.00494 AC XY: 368 AN XY: 74508

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.0135

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.0318

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.00772

Gnomad4 NFE AF: 0.00235

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00276 Hom.: 5

Bravo AF: 0.00575

Asia WGS AF: 0.0170 AC: 59 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	14
DANN	Uncertain	0.97

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs28365950; hg19: chr19-13049415;