Genetic Variant RCBTB1:p.Leu215Met (chr13-49552246-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_018191.4(RCBTB1):c.643C>A(p.Leu215Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L215L) has been classified as Benign.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RCBTB1
NM_018191.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.881

Publications

23 publications found

Variant links:

Genes affected

RCBTB1 (HGNC:18243): (RCC1 and BTB domain containing protein 1) This gene encodes a protein with an N-terminal RCC1 domain and a C-terminal BTB (broad complex, tramtrack and bric-a-brac) domain. In rat, over-expression of this gene in vascular smooth muscle cells induced cellular hypertrophy. In rat, the C-terminus of RCBTB1 interacts with the angiotensin II receptor-1A. In humans, this gene maps to a region of chromosome 13q that is frequently deleted in B-cell chronic lymphocytic leukemia and other lymphoid malignancies. [provided by RefSeq, Jul 2008]

RCBTB1 Gene-Disease associations (from GenCC):

RCBTB1-related retinopathy
Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
reticular dystrophy of the retinal pigment epithelium
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
exudative vitreoretinopathy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, G2P

RCBTB1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RCBTB1	NM_018191.4 link	c.643C>A	p.Leu215Met	missense_variant	Exon 7 of 13	ENST00000378302.7	NP_060661.3	Q8NDN9-1B3KR20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RCBTB1	ENST00000378302.7 link	c.643C>A	p.Leu215Met	missense_variant	Exon 7 of 13	1	NM_018191.4	ENSP00000367552.2	Q8NDN9-1
RCBTB1	ENST00000258646.3 link	c.643C>A	p.Leu215Met	missense_variant	Exon 5 of 11	2		ENSP00000258646.3	Q8NDN9-1
RCBTB1	ENST00000490058.1 link	n.7C>A		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1450672

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720408

African (AFR)

AF:

0.00

AC:

AN:

33360

American (AMR)

AF:

0.00

AC:

AN:

43350

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25810

East Asian (EAS)

AF:

0.00

AC:

AN:

39548

South Asian (SAS)

AF:

0.00

AC:

AN:

84174

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52544

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5632

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106288

Other (OTH)

AF:

0.00

AC:

AN:

59966

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.045

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

T;T

Eigen

Benign

0.080

Eigen_PC

Benign

-0.0024

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.92

.;D

M_CAP

Uncertain

0.090

MetaRNN

Uncertain

0.68

D;D

MetaSVM

Uncertain

0.22

MutationAssessor

Uncertain

2.4

M;M

PhyloP100

0.88

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.0

N;N

REVEL

Uncertain

0.52

Sift

Benign

0.12

T;T

Sift4G

Uncertain

0.033

D;D

Polyphen

0.98

D;D

Vest4

0.48

MutPred

0.64

Gain of catalytic residue at N210 (P = 0.0099);Gain of catalytic residue at N210 (P = 0.0099);

MVP

0.91

MPC

0.68

ClinPred

0.93

GERP RS

0.34

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.37

Mutation Taster

=75/25

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over