19-16482507-C-T

Variant names:

• chr19-16482507-C-T
• rs118131979
• NM_145046.5:c.861G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_145046.5(CALR3):​c.861G>A​(p.Thr287Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 1,614,202 control chromosomes in the GnomAD database, including 212 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (15 hom., cov: 33)
  • Exomes 𝑓: 0.015 (197 hom.)
• Consequence: CALR3 NM_145046.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -7.85
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 19-16482507-C-T is Benign according to our data. Variant chr19-16482507-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-7.85 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0117 (1775/152328) while in subpopulation NFE AF = 0.016 (1091/68034). AF 95% confidence interval is 0.0152. There are 15 homozygotes in GnomAd4. There are 951 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1775 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.861G>A	p.Thr287Thr	synonymous	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.861G>A	p.Thr287Thr	synonymous	Exon 7 of 9	ENSP00000269881.3	Q96L12
	ENSG00000141979	ENST00000409035.1	TSL:2	n.*664G>A		non_coding_transcript_exon	Exon 10 of 12	ENSP00000386951.2	B8ZZF3
	ENSG00000141979	ENST00000409035.1	TSL:2	n.*664G>A		3_prime_UTR	Exon 10 of 12	ENSP00000386951.2	B8ZZF3

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1772 AN: 152210 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.0136

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00911

Gnomad FIN AF: 0.0392

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0160

Gnomad OTH AF: 0.00812

GnomAD2 exomes AF: 0.0122 AC: 3060 AN: 251488 AF XY: 0.0123

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00286

Gnomad ASJ exome AF: 0.0112

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0361

Gnomad NFE exome AF: 0.0150

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.0148 AC: 21571 AN: 1461874 Hom.: 197 Cov.: 45 AF XY: 0.0147 AC XY: 10726 AN XY: 727240

African (AFR) AF: 0.00122 AC: 41 AN: 33480

American (AMR) AF: 0.00291 AC: 130 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 272 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00949 AC: 819 AN: 86258

European-Finnish (FIN) AF: 0.0371 AC: 1979 AN: 53414

Middle Eastern (MID) AF: 0.00589 AC: 34 AN: 5768

European-Non Finnish (NFE) AF: 0.0158 AC: 17616 AN: 1112000

Other (OTH) AF: 0.0112 AC: 679 AN: 60396

GnomAD4 genome AF: 0.0117 AC: 1775 AN: 152328 Hom.: 15 Cov.: 33 AF XY: 0.0128 AC XY: 951 AN XY: 74494

African (AFR) AF: 0.00250 AC: 104 AN: 41582

American (AMR) AF: 0.00314 AC: 48 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0136 AC: 47 AN: 3468

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

South Asian (SAS) AF: 0.00974 AC: 47 AN: 4826

European-Finnish (FIN) AF: 0.0392 AC: 416 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0160 AC: 1091 AN: 68034

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.0139 Hom.: 27

Bravo AF: 0.00823

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0150

EpiControl AF: 0.0133

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hypertrophic cardiomyopathy 19 (3)
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.052
DANN	Benign	0.45
PhyloP100		-7.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs118131979; hg19: chr19-16593318; COSMIC: COSV108072479; COSMIC: COSV108072479;