Genetic Variant CBR3:p.Glu124Lys (chr21-36137905-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001236.4(CBR3):c.370G>A(p.Glu124Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,607,494 control chromosomes in the GnomAD database, including 42 homozygotes. 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 Benign (★).

Frequency

Genomes: 𝑓 0.00064 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 38 hom. )

Consequence

CBR3
NM_001236.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.36

Variant links:

Genes affected

CBR3 (HGNC:1549): (carbonyl reductase 3) Carbonyl reductase 3 catalyzes the reduction of a large number of biologically and pharmacologically active carbonyl compounds to their corresponding alcohols. The enzyme is classified as a monomeric NADPH-dependent oxidoreductase. CBR3 contains three exons spanning 11.2 kilobases and is closely linked to another carbonyl reductase gene - CBR1. [provided by RefSeq, Jul 2008]

CBR3 links:

CBR3-AS1 (HGNC:43664): (CBR3 antisense RNA 1)

CBR3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008440495).

BP6

Variant 21-36137905-G-A is Benign according to our data. Variant chr21-36137905-G-A is described in ClinVar as [Benign]. Clinvar id is 773089.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000644 (98/152226) while in subpopulation SAS AF= 0.0189 (91/4822). AF 95% confidence interval is 0.0157. There are 4 homozygotes in gnomad4. There are 75 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CBR3	NM_001236.4 link	c.370G>A	p.Glu124Lys	missense_variant	Exon 2 of 3	ENST00000290354.6	NP_001227.1
CBR3	XM_011529772.3 link	c.370G>A	p.Glu124Lys	missense_variant	Exon 2 of 3		XP_011528074.1
CBR3-AS1	NR_038892.1 link	n.193-4144C>T		intron_variant	Intron 2 of 3
CBR3-AS1	NR_038893.1 link	n.193-4831C>T		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBR3	ENST00000290354.6 link	c.370G>A	p.Glu124Lys	missense_variant	Exon 2 of 3	1	NM_001236.4	ENSP00000290354.5		O75828

Frequencies

GnomAD3 genomes

AF:

0.000644

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0189

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00235

AC:

590

AN:

251012

Hom.:

AF XY:

0.00317

AC XY:

430

AN XY:

135788

show subpopulations

Gnomad AFR exome

AF:

0.000309

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0188

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.00121

AC:

1762

AN:

1455268

Hom.:

Cov.:

AF XY:

0.00179

AC XY:

1296

AN XY:

724432

show subpopulations

Gnomad4 AFR exome

AF:

0.000240

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0192

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000118

Gnomad4 OTH exome

AF:

0.00125

GnomAD4 genome

AF:

0.000644

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0189

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000199

Hom.:

Bravo

AF:

0.000121

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.00250

AC:

303

Asia WGS

AF:

0.00837

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 08, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.47

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.45

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0084

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.75

PrimateAI

Benign

0.48

PROVEAN

Benign

-2.0

REVEL

Benign

0.15

Sift

Benign

0.50

Sift4G

Benign

0.65

Polyphen

0.017

Vest4

0.40

MutPred

0.63

Gain of MoRF binding (P = 0.0271);

MVP

0.47

MPC

0.22

ClinPred

0.022

GERP RS

4.5

Varity_R

0.24

gMVP

0.52

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