rs190251647

Variant names:

• chr19-12938676-C-T
• rs190251647
• NM_004343.4:c.-4C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-12938676-C-T
• chr19-12938676-C-A
• chr19-12938676-C-G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_004343.4(CALR):​c.-4C>T 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 0.00139 in 1,607,766 control chromosomes in the GnomAD database, including 46 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (36 hom.)
• Consequence: CALR NM_004343.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.115
• Publications: 3 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 -10 ACMG points.

• BP6: Variant 19-12938676-C-T is Benign according to our data. Variant chr19-12938676-C-T is described in ClinVar as Benign. ClinVar VariationId is 1269519.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00198 (301/152368) while in subpopulation EAS AF = 0.0521 (270/5180). AF 95% confidence interval is 0.047. There are 10 homozygotes in GnomAd4. There are 184 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 301 AD gene.

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.-4C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	NP_004334.1	P27797
	CALR	NM_004343.4	MANE Select	c.-4C>T		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.-4C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	ENSP00000320866.4	P27797
	CALR	ENST00000316448.10	TSL:1 MANE Select	c.-4C>T		5_prime_UTR	Exon 1 of 9	ENSP00000320866.4	P27797
	CALR	ENST00000957023.1		c.-4C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	ENSP00000627082.1

Frequencies

GnomAD3 genomes AF: 0.00198 AC: 302 AN: 152250 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.0520

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00458 AC: 1065 AN: 232634 AF XY: 0.00438

Gnomad AFR exome AF: 0.000146

Gnomad AMR exome AF: 0.000178

Gnomad ASJ exome AF: 0.00550

Gnomad EAS exome AF: 0.0558

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000680

Gnomad OTH exome AF: 0.00122

GnomAD4 exome AF: 0.00132 AC: 1928 AN: 1455398 Hom.: 36 Cov.: 31 AF XY: 0.00136 AC XY: 982 AN XY: 723650

African (AFR) AF: 0.000120 AC: 4 AN: 33344

American (AMR) AF: 0.0000678 AC: 3 AN: 44220

Ashkenazi Jewish (ASJ) AF: 0.00393 AC: 102 AN: 25972

East Asian (EAS) AF: 0.0399 AC: 1571 AN: 39414

South Asian (SAS) AF: 0.000784 AC: 67 AN: 85510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51696

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1109452

Other (OTH) AF: 0.00250 AC: 150 AN: 60050

GnomAD4 genome AF: 0.00198 AC: 301 AN: 152368 Hom.: 10 Cov.: 32 AF XY: 0.00247 AC XY: 184 AN XY: 74508

African (AFR) AF: 0.0000481 AC: 2 AN: 41592

American (AMR) AF: 0.000131 AC: 2 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.0521 AC: 270 AN: 5180

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4832

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: 0.0000588 AC: 4 AN: 68036

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000914 Hom.: 1

Bravo AF: 0.00298

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

ClinVar submissions

Significance: 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	Uncertain	-0.080
CADD	Benign	22
DANN	Benign	0.96
PhyloP100		0.12
PromoterAI		-0.17	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=299/1	polymorphism

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: rs190251647; hg19: chr19-13049490; COSMIC: COSV57132556; COSMIC: COSV57132556;