chr19-12938659-T-C

Variant names:

• chr19-12938659-T-C
• rs11547567
• NM_004343.4:c.-21T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 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 -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004343.4. 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.-21T>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	NP_004334.1	P27797
	CALR	NM_004343.4	MANE Select	c.-21T>C		5_prime_UTR	Exon 1 of 9	NP_004334.1	P27797

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALR	ENST00000316448.10	TSL:1 MANE Select	c.-21T>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	ENSP00000320866.4	P27797
	CALR	ENST00000316448.10	TSL:1 MANE Select	c.-21T>C		5_prime_UTR	Exon 1 of 9	ENSP00000320866.4	P27797
	CALR	ENST00000957023.1		c.-21T>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	ENSP00000627082.1

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

GnomAD2 exomes AF: 0.0122 AC: 2682 AN: 219052 AF XY: 0.00926

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 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

African (AFR) AF: 0.198 AC: 6511 AN: 32966

American (AMR) AF: 0.00968 AC: 415 AN: 42864

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25760

East Asian (EAS) AF: 0.0000258 AC: 1 AN: 38832

South Asian (SAS) AF: 0.000225 AC: 19 AN: 84448

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50958

Middle Eastern (MID) AF: 0.00583 AC: 33 AN: 5658

European-Non Finnish (NFE) AF: 0.000200 AC: 220 AN: 1100278

Other (OTH) AF: 0.0120 AC: 713 AN: 59482

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

African (AFR) AF: 0.189 AC: 7833 AN: 41528

American (AMR) AF: 0.0165 AC: 253 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68010

Other (OTH) AF: 0.0360 AC: 76 AN: 2114

Alfa AF: 0.0313 Hom.: 83

Bravo AF: 0.0605

Asia WGS AF: 0.0140 AC: 49 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	14
DANN	Benign	0.80
PhyloP100		-0.27
PromoterAI		-0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11547567; hg19: chr19-13049473;