rs75099211

Variant names:

• chr19-16482520-G-A
• rs75099211
• NM_145046.5:c.848C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_145046.5(CALR3):​c.848C>T​(p.Thr283Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000231 in 1,614,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T283T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: CALR3 NM_145046.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 7.17
• Publications: 1 publications found

Genes affected

CALR3 (HGNC:20407): (calreticulin 3) The protein encoded by this gene belongs to the calreticulin family, members of which are calcium-binding chaperones localized mainly in the endoplasmic reticulum. This protein is also localized to the endoplasmic reticulum lumen, however, its capacity for calcium-binding may be absent or much lower than other family members. This gene is specifically expressed in the testis, and may be required for sperm fertility. Mutation in this gene has been associated with familial hypertrophic cardiomyopathy. [provided by RefSeq, Dec 2011]

CALR3 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000141979 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006067902).
• BP6: Variant 19-16482520-G-A is Benign according to our data. Variant chr19-16482520-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 416239.
• BS2: High AC in GnomAd4 at 201 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145046.5. 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
	CALR3	NM_145046.5	MANE Select	c.848C>T	p.Thr283Ile	missense	Exon 7 of 9	NP_659483.2	A0A140VJF7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALR3	ENST00000269881.8	TSL:1 MANE Select	c.848C>T	p.Thr283Ile	missense	Exon 7 of 9	ENSP00000269881.3	Q96L12
	ENSG00000141979	ENST00000409035.1	TSL:2	n.*651C>T		non_coding_transcript_exon	Exon 10 of 12	ENSP00000386951.2	B8ZZF3
	ENSG00000141979	ENST00000409035.1	TSL:2	n.*651C>T		3_prime_UTR	Exon 10 of 12	ENSP00000386951.2	B8ZZF3

Frequencies

GnomAD3 genomes AF: 0.00132 AC: 201 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00463

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000362 AC: 91 AN: 251496 AF XY: 0.000346

Gnomad AFR exome AF: 0.00535

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000118 AC: 172 AN: 1461884 Hom.: 0 Cov.: 46 AF XY: 0.000103 AC XY: 75 AN XY: 727244

African (AFR) AF: 0.00448 AC: 150 AN: 33480

American (AMR) AF: 0.000157 AC: 7 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112004

Other (OTH) AF: 0.000248 AC: 15 AN: 60396

GnomAD4 genome AF: 0.00132 AC: 201 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.00130 AC XY: 97 AN XY: 74480

African (AFR) AF: 0.00462 AC: 192 AN: 41564

American (AMR) AF: 0.000392 AC: 6 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000549 Hom.: 1

Bravo AF: 0.00151

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000404 AC: 49

Asia WGS AF: 0.000577 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	1	-	Cardiovascular phenotype (1)
-	1	-	Hypertrophic cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy 19 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		7.2
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.66	P
Vest4		0.29
MVP		0.26
MPC		0.49
ClinPred		0.15	T
GERP RS		2.8
Varity_R		0.30
gMVP		0.50
Mutation Taster		=87/13	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: rs75099211; hg19: chr19-16593331;