11-63911944-C-G

Variant names:

• chr11-63911944-C-G
• rs946033018
• NM_173587.4:c.1493G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173587.4(RCOR2):​c.1493G>C​(p.Arg498Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 76,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. R498H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 21)
  • Exomes 𝑓: 0.000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RCOR2 NM_173587.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.29
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12165764).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173587.4. 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
	RCOR2	NM_173587.4	MANE Select	c.1493G>C	p.Arg498Pro	missense	Exon 12 of 12	NP_775858.2	Q8IZ40
	RCOR2	NM_001363648.2		c.1263G>C	p.Pro421Pro	synonymous	Exon 11 of 11	NP_001350577.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RCOR2	ENST00000301459.5	TSL:1 MANE Select	c.1493G>C	p.Arg498Pro	missense	Exon 12 of 12	ENSP00000301459.4	Q8IZ40
	RCOR2	ENST00000864867.1		c.1496G>C	p.Arg499Pro	missense	Exon 13 of 13	ENSP00000534926.1
	RCOR2	ENST00000917267.1		c.1493G>C	p.Arg498Pro	missense	Exon 13 of 13	ENSP00000587326.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 1 AN: 76454 Hom.: 0 Cov.: 21

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000281

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000136 AC: 8 AN: 586558 Hom.: 0 Cov.: 15 AF XY: 0.0000208 AC XY: 6 AN XY: 288626

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 12130

American (AMR) AF: 0.00 AC: 0 AN: 9256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7728

East Asian (EAS) AF: 0.00 AC: 0 AN: 10674

South Asian (SAS) AF: 0.0000244 AC: 1 AN: 41046

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10026

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1504

European-Non Finnish (NFE) AF: 0.0000149 AC: 7 AN: 471346

Other (OTH) AF: 0.00 AC: 0 AN: 22848

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000831674), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000131 AC: 1 AN: 76454 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 37018

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 20022

American (AMR) AF: 0.00 AC: 0 AN: 8204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1976

East Asian (EAS) AF: 0.00 AC: 0 AN: 2808

South Asian (SAS) AF: 0.00 AC: 0 AN: 2022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4080

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.0000281 AC: 1 AN: 35548

Other (OTH) AF: 0.00 AC: 0 AN: 1118

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.3
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	0.060	N
REVEL	Benign	0.12
Sift	Benign	0.033	D
Sift4G	Benign	0.30	T
Polyphen		0.016	B
Vest4		0.13
MutPred		0.24		Gain of glycosylation at R498 (P = 0.0101)
MVP		0.40
MPC		1.3
ClinPred		0.86	D
GERP RS		4.4
Varity_R		0.24
gMVP		0.34
Mutation Taster		=78/22	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: rs946033018; hg19: chr11-63679416; COSMIC: COSV105013113; COSMIC: COSV105013113;