Genetic Variant RCOR2:p.Arg431Gln (chr11-63912145-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_173587.4(RCOR2):c.1292G>A(p.Arg431Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 1,527,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R431G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

RCOR2
NM_173587.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.04

Variant links:

Genes affected

RCOR2 (HGNC:27455): (REST corepressor 2) Predicted to enable transcription corepressor activity. Predicted to be involved in histone deacetylation; negative regulation of transcription, DNA-templated; and regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. Predicted to be part of histone deacetylase complex and transcription regulator complex. [provided by Alliance of Genome Resources, Apr 2022]

RCOR2 links:

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ACMG classification

Classification made for transcript

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=0.08477017).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RCOR2	NM_173587.4 link	c.1292G>A	p.Arg431Gln	missense_variant	Exon 12 of 12	ENST00000301459.5	NP_775858.2	Q8IZ40
RCOR2	XM_047426828.1 link	c.1484G>A	p.Arg495Gln	missense_variant	Exon 14 of 14		XP_047282784.1
RCOR2	NM_001363648.2 link	c.1062G>A	p.Pro354Pro	synonymous_variant	Exon 11 of 11		NP_001350577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RCOR2	ENST00000301459.5 link	c.1292G>A	p.Arg431Gln	missense_variant	Exon 12 of 12	1	NM_173587.4	ENSP00000301459.4	Q8IZ40
RCOR2	ENST00000473926.2 link	n.86G>A		non_coding_transcript_exon_variant	Exon 2 of 2	3
RCOR2	ENST00000489217.1 link	n.535G>A		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.000119

AC:

AN:

151122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000488

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:

0.000191

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000207

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000109

AC:

AN:

127892

Hom.:

AF XY:

0.000116

AC XY:

AN XY:

69198

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000101

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000226

Gnomad NFE exome

AF:

0.000197

Gnomad OTH exome

AF:

0.000263

GnomAD4 exome

AF:

0.000183

AC:

252

AN:

1376424

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

137

AN XY:

679486

show subpopulations

Gnomad4 AFR exome

AF:

0.0000979

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000558

Gnomad4 SAS exome

AF:

0.000169

Gnomad4 FIN exome

AF:

0.0000996

Gnomad4 NFE exome

AF:

0.000207

Gnomad4 OTH exome

AF:

0.000140

GnomAD4 genome

AF:

0.000119

AC:

AN:

151122

Hom.:

Cov.:

AF XY:

0.0000949

AC XY:

AN XY:

73752

show subpopulations

Gnomad4 AFR

AF:

0.0000488

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000191

Gnomad4 NFE

AF:

0.000207

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000855

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.0000190

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1292G>A (p.R431Q) alteration is located in exon 12 (coding exon 12) of the RCOR2 gene. This alteration results from a G to A substitution at nucleotide position 1292, causing the arginine (R) at amino acid position 431 to be replaced by a glutamine (Q). 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

0.080

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.014

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.84

M_CAP

Benign

0.014

MetaRNN

Benign

0.085

MetaSVM

Benign

-1.1

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.20

REVEL

Benign

0.074

Sift

Benign

0.30

Sift4G

Benign

0.52

Polyphen

0.023

Vest4

0.13

MVP

0.43

MPC

1.0

ClinPred

0.24

GERP RS

4.7

Varity_R

0.087

gMVP

0.31

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over