NM_145046.5:c.691C>G

Variant names:

• chr19-16482773-G-C
• rs1555775874
• NM_145046.5:c.691C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_145046.5(CALR3):​c.691C>G​(p.His231Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,613,018 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CALR3 NM_145046.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.80
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.691C>G	p.His231Asp	missense	Exon 6 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.691C>G	p.His231Asp	missense	Exon 6 of 9	ENSP00000269881.3	Q96L12
	ENSG00000141979	ENST00000409035.1	TSL:2	n.*494C>G		non_coding_transcript_exon	Exon 9 of 12	ENSP00000386951.2	B8ZZF3
	ENSG00000141979	ENST00000409035.1	TSL:2	n.*494C>G		3_prime_UTR	Exon 9 of 12	ENSP00000386951.2	B8ZZF3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460834 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 726678

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5260

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111750

Other (OTH) AF: 0.00 AC: 0 AN: 60302

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74330

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.0000655 AC: 1 AN: 15256

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hypertrophic cardiomyopathy 19 (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.26
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.085	T
Polyphen		0.99	D
Vest4		0.24
MutPred		0.74		Gain of relative solvent accessibility (P = 0.0999)
MVP		0.65
MPC		0.56
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.46
gMVP		0.71
Mutation Taster		=27/73	disease causing

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: rs1555775874; hg19: chr19-16593584;