19-12938601-C-T

Variant names:

• chr19-12938601-C-T
• rs28365950
• ENST00000587486.6:n.24C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 692 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000587486.6. 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
	CALR	NM_004343.4	MANE Select	c.-79C>T		upstream_gene	N/A	NP_004334.1	P27797

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALR	ENST00000587486.6	TSL:2	n.24C>T		non_coding_transcript_exon	Exon 1 of 3
	CALR	ENST00000316448.10	TSL:1 MANE Select	c.-79C>T		upstream_gene	N/A	ENSP00000320866.4	P27797
	CALR	ENST00000957023.1		c.-79C>T		upstream_gene	N/A	ENSP00000627082.1

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

African (AFR) AF: 0.000741 AC: 17 AN: 22944

American (AMR) AF: 0.0252 AC: 883 AN: 35038

Ashkenazi Jewish (ASJ) AF: 0.00394 AC: 88 AN: 22358

East Asian (EAS) AF: 0.0349 AC: 1177 AN: 33710

South Asian (SAS) AF: 0.00381 AC: 268 AN: 70432

European-Finnish (FIN) AF: 0.0106 AC: 469 AN: 44432

Middle Eastern (MID) AF: 0.00148 AC: 5 AN: 3368

European-Non Finnish (NFE) AF: 0.00179 AC: 1218 AN: 682182

Other (OTH) AF: 0.00461 AC: 200 AN: 43342

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

African (AFR) AF: 0.000818 AC: 34 AN: 41588

American (AMR) AF: 0.0135 AC: 206 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.0318 AC: 165 AN: 5192

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4830

European-Finnish (FIN) AF: 0.00772 AC: 82 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00235 AC: 160 AN: 68028

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00322 Hom.: 7

Bravo AF: 0.00575

Asia WGS AF: 0.0170 AC: 59 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	14
DANN	Uncertain	0.97
PhyloP100		0.43
PromoterAI		-0.061	Neutral

Splicing

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

Other links and lift over

dbSNP: rs28365950; hg19: chr19-13049415;