19-49534215-C-A

Variant names:

• chr19-49534215-C-A
• NM_020650.3:c.265C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020650.3(RCN3):​c.265C>A​(p.Arg89Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000748 in 1,336,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: RCN3 NM_020650.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.559

Genes affected

RCN3 (HGNC:21145): (reticulocalbin 3) Enables calcium ion binding activity. Involved in several processes, including collagen biosynthetic process; positive regulation of peptidase activity; and regulation of protein kinase B signaling. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18704036).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RCN3	NM_020650.3	c.265C>A	p.Arg89Ser	missense_variant	Exon 3 of 7	ENST00000270645.8	NP_065701.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RCN3	ENST00000270645.8	c.265C>A	p.Arg89Ser	missense_variant	Exon 3 of 7	1	NM_020650.3	ENSP00000270645.2
RCN3	ENST00000598833.1	c.112C>A	p.Arg38Ser	missense_variant	Exon 2 of 4	3		ENSP00000470540.1
RCN3	ENST00000597801.1	c.265C>A	p.Arg89Ser	missense_variant	Exon 3 of 4	5		ENSP00000469727.1
RCN3	ENST00000593644.1	n.172-2818C>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.48e-7 AC: 1 AN: 1336300 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 656424

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000307

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.265C>A (p.R89S) alteration is located in exon 3 (coding exon 2) of the RCN3 gene. This alteration results from a C to A substitution at nucleotide position 265, causing the arginine (R) at amino acid position 89 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.0011	T;T;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.71	T;T;T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.50	N;.;.
REVEL	Benign	0.098
Sift	Benign	0.053	T;.;.
Sift4G	Benign	0.42	T;T;T
Polyphen		0.0040	B;.;.
Vest4		0.19
MutPred		0.44		Loss of MoRF binding (P = 0.0227);Loss of MoRF binding (P = 0.0227);.;
MVP		0.66
MPC		0.86
ClinPred		0.14	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.45

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-50037472;