rs7246836

Variant names:

• chr19-12939276-C-G
• rs7246836
• NM_004343.4:c.193+41C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-12939276-C-G
• chr19-12939276-C-A
• chr19-12939276-C-T

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.193+41C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.01 in 1,488,674 control chromosomes in the GnomAD database, including 1,311 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (697 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (614 hom.)
• Consequence: CALR NM_004343.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0960
• Publications: 2 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=-0.77).
• BP6: Variant 19-12939276-C-G is Benign according to our data. Variant chr19-12939276-C-G is described in ClinVar as Benign. ClinVar VariationId is 1257047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.175 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.193+41C>G		intron	N/A	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.193+41C>G		intron	N/A	ENSP00000320866.4	P27797
	CALR	ENST00000957023.1		c.193+41C>G		intron	N/A	ENSP00000627082.1
	CALR	ENST00000929790.1		c.193+41C>G		intron	N/A	ENSP00000599849.1

Frequencies

GnomAD3 genomes AF: 0.0510 AC: 7759 AN: 152046 Hom.: 698 Cov.: 32

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0162

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0359

GnomAD2 exomes AF: 0.0129 AC: 2695 AN: 209264 AF XY: 0.00959

Gnomad AFR exome AF: 0.190

Gnomad AMR exome AF: 0.00844

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000263

Gnomad OTH exome AF: 0.00499

GnomAD4 exome AF: 0.00534 AC: 7133 AN: 1336510 Hom.: 614 Cov.: 20 AF XY: 0.00454 AC XY: 3037 AN XY: 668542

African (AFR) AF: 0.189 AC: 5852 AN: 30984

American (AMR) AF: 0.00993 AC: 391 AN: 39372

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24926

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38674

South Asian (SAS) AF: 0.000233 AC: 19 AN: 81694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52014

Middle Eastern (MID) AF: 0.00578 AC: 32 AN: 5538

European-Non Finnish (NFE) AF: 0.000193 AC: 194 AN: 1007018

Other (OTH) AF: 0.0114 AC: 644 AN: 56290

GnomAD4 genome AF: 0.0510 AC: 7760 AN: 152164 Hom.: 697 Cov.: 32 AF XY: 0.0494 AC XY: 3671 AN XY: 74380

African (AFR) AF: 0.179 AC: 7414 AN: 41480

American (AMR) AF: 0.0161 AC: 246 AN: 15272

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68008

Other (OTH) AF: 0.0355 AC: 75 AN: 2114

Alfa AF: 0.00841 Hom.: 16

Bravo AF: 0.0578

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	-0.77
CADD	Benign	8.8
DANN	Benign	0.76
PhyloP100		-0.096
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=100/0	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: rs7246836; hg19: chr19-13050090;