19-49539123-C-A

Variant names:

• chr19-49539123-C-A
• rs146820947
• NM_020650.3:c.623C>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_020650.3(RCN3):​c.623C>A​(p.Thr208Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000384 in 1,602,784 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T208I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00039 (6 hom.)
• Consequence: RCN3 NM_020650.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.97
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016086698).
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020650.3. 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
	RCN3	NM_020650.3	MANE Select	c.623C>A	p.Thr208Asn	missense	Exon 5 of 7	NP_065701.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RCN3	ENST00000270645.8	TSL:1 MANE Select	c.623C>A	p.Thr208Asn	missense	Exon 5 of 7	ENSP00000270645.2	Q96D15
	RCN3	ENST00000892641.1		c.734C>A	p.Thr245Asn	missense	Exon 5 of 7	ENSP00000562700.1
	RCN3	ENST00000956869.1		c.734C>A	p.Thr245Asn	missense	Exon 4 of 6	ENSP00000626928.1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152080 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00934

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000614 AC: 148 AN: 241116 AF XY: 0.000856

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000907

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000393 AC: 570 AN: 1450586 Hom.: 6 Cov.: 30 AF XY: 0.000576 AC XY: 416 AN XY: 721862

African (AFR) AF: 0.0000304 AC: 1 AN: 32940

American (AMR) AF: 0.00 AC: 0 AN: 41838

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25552

East Asian (EAS) AF: 0.00 AC: 0 AN: 39020

South Asian (SAS) AF: 0.00632 AC: 536 AN: 84788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53134

Middle Eastern (MID) AF: 0.000525 AC: 3 AN: 5716

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1107744

Other (OTH) AF: 0.000251 AC: 15 AN: 59854

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152198 Hom.: 0 Cov.: 31 AF XY: 0.000470 AC XY: 35 AN XY: 74396

African (AFR) AF: 0.00 AC: 0 AN: 41540

American (AMR) AF: 0.00 AC: 0 AN: 15262

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00935 AC: 45 AN: 4814

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: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000254 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.000749 AC: 91

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000547

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.044	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		3.0
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.64
MutPred		0.51		Loss of phosphorylation at T208 (P = 0.029)
MVP		0.83
MPC		0.14
ClinPred		0.28	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.89
gMVP		0.86
Mutation Taster		=96/4	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: rs146820947; hg19: chr19-50042380;