Genetic Variant RCOR1:p.Ala30dup (chr14-102592962-T-TCCG) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3BS1_SupportingBS2

The NM_015156.4(RCOR1):c.88_90dupGCC(p.Ala30dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000983 in 1,166,100 control chromosomes in the GnomAD database, including 25 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S31S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0012 ( 4 hom., cov: 33)

Exomes 𝑓: 0.00095 ( 21 hom. )

Consequence

RCOR1
NM_015156.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.608

Variant links:

Genes affected

RCOR1 (HGNC:17441): (REST corepressor 1) This gene encodes a protein that is well-conserved, downregulated at birth, and with a specific role in determining neural cell differentiation. The encoded protein binds to the C-terminal domain of REST (repressor element-1 silencing transcription factor). [provided by RefSeq, Aug 2011]

RCOR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_015156.4

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00122 (179/146844) while in subpopulation SAS AF = 0.0333 (159/4776). AF 95% confidence interval is 0.0291. There are 4 homozygotes in GnomAd4. There are 132 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 179 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RCOR1	NM_015156.4 link	c.88_90dupGCC	p.Ala30dup	conservative_inframe_insertion	Exon 1 of 12	ENST00000262241.7	NP_055971.2	Q9UKL0
RCOR1	XM_047431148.1 link	c.88_90dupGCC	p.Ala30dup	conservative_inframe_insertion	Exon 1 of 10		XP_047287104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RCOR1	ENST00000262241.7 link	c.88_90dupGCC	p.Ala30dup	conservative_inframe_insertion	Exon 1 of 12	1	NM_015156.4	ENSP00000262241.5		Q9UKL0

Frequencies

GnomAD3 genomes

AF:

0.00123

AC:

180

AN:

146734

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000740

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000393

Gnomad SAS

AF:

0.0335

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000198

Gnomad OTH

AF:

0.000990

GnomAD2 exomes

AF:

0.00400

AC:

AN:

22264

AF XY:

0.00563

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000949

AC:

967

AN:

1019256

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

585

AN XY:

491686

show subpopulations

Gnomad4 AFR exome

AF:

0.0000504

AC:

AN:

19844

Gnomad4 AMR exome

AF:

0.000233

AC:

AN:

8576

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

12538

Gnomad4 EAS exome

AF:

0.000830

AC:

AN:

15662

Gnomad4 SAS exome

AF:

0.0250

AC:

746

AN:

29800

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

16890

Gnomad4 NFE exome

AF:

0.000144

AC:

126

AN:

875576

Gnomad4 Remaining exome

AF:

0.00185

AC:

AN:

37808

Heterozygous variant carriers

128

170

213

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00122

AC:

179

AN:

146844

Hom.:

Cov.:

AF XY:

0.00184

AC XY:

132

AN XY:

71626

show subpopulations

Gnomad4 AFR

AF:

0.0000738

AC:

0.0000738334

AN:

0.0000738334

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.000395

AC:

0.000394633

AN:

0.000394633

Gnomad4 SAS

AF:

0.0333

AC:

0.0332915

AN:

0.0332915

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000198

AC:

0.000197677

AN:

0.000197677

Gnomad4 OTH

AF:

0.000978

AC:

0.000978474

AN:

0.000978474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.88_90dup, results in the insertion of 1 amino acid(s) of the RCOR1 protein (p.Ala30dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RCOR1-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=78/22

polymorphism

Splicing

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