chr19-49542666-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The ENST00000270645.8(RCN3):​c.793G>A​(p.Glu265Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000194 in 1,601,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

RCN3
ENST00000270645.8 missense

Scores

11
6
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.91
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a binding_site (size 0) in uniprot entity RCN3_HUMAN
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RCN3NM_020650.3 linkuse as main transcriptc.793G>A p.Glu265Lys missense_variant 6/7 ENST00000270645.8 NP_065701.2 Q96D15

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RCN3ENST00000270645.8 linkuse as main transcriptc.793G>A p.Glu265Lys missense_variant 6/71 NM_020650.3 ENSP00000270645.2 Q96D15
RCN3ENST00000593483.1 linkuse as main transcriptc.64G>A p.Glu22Lys missense_variant, splice_region_variant 1/25 ENSP00000470771.1 M0QZU3
RCN3ENST00000598833.1 linkuse as main transcriptc.466-4155G>A intron_variant 3 ENSP00000470540.1 M0QZH0

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152212
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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
GnomAD3 exomes
AF:
0.0000179
AC:
4
AN:
223572
Hom.:
0
AF XY:
0.0000249
AC XY:
3
AN XY:
120422
show subpopulations
Gnomad AFR exome
AF:
0.0000720
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000366
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000197
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000207
AC:
30
AN:
1448842
Hom.:
0
Cov.:
32
AF XY:
0.0000209
AC XY:
15
AN XY:
719198
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000599
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000217
Gnomad4 OTH exome
AF:
0.0000167
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152212
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 04, 2023The c.793G>A (p.E265K) alteration is located in exon 6 (coding exon 5) of the RCN3 gene. This alteration results from a G to A substitution at nucleotide position 793, causing the glutamic acid (E) at amino acid position 265 to be replaced by a lysine (K). 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
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Pathogenic
0.32
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.35
T
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.88
D
M_CAP
Uncertain
0.13
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Uncertain
0.47
D
MutationAssessor
Pathogenic
3.1
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.61
T
PROVEAN
Uncertain
-3.8
D
REVEL
Pathogenic
0.79
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0040
D
Polyphen
0.99
D
Vest4
1.0
MutPred
0.86
Gain of ubiquitination at E265 (P = 0.0192);
MVP
0.91
MPC
0.057
ClinPred
0.96
D
GERP RS
5.1
Varity_R
0.83
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.23
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.23
Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1326791405; hg19: chr19-50045923; API