rs1056892

Positions:

• chr21-36146408-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001236.4(CBR3):​c.730G>A​(p.Val244Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.369 in 1,613,776 control chromosomes in the GnomAD database, including 112,002 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.39 (11709 hom., cov: 32)
  • Exomes 𝑓: 0.37 (100293 hom.)
• Consequence: CBR3 NM_001236.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.87

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

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001534909).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.482 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBR3	NM_001236.4	c.730G>A	p.Val244Met	missense_variant	3/3	ENST00000290354.6
CBR3-AS1	NR_038893.1	n.93-53C>T		intron_variant, non_coding_transcript_variant
CBR3-AS1	NR_038892.1	n.93-53C>T		intron_variant, non_coding_transcript_variant
CBR3-AS1	NR_038894.1	n.93-53C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBR3	ENST00000290354.6	c.730G>A	p.Val244Met	missense_variant	3/3	1	NM_001236.4	P1
CBR3-AS1	ENST00000624080.1	n.149-12935C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58757 AN: 151888 Hom.: 11707 Cov.: 32

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.404

Gnomad SAS AF: 0.499

Gnomad FIN AF: 0.329

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.357

Gnomad OTH AF: 0.365

GnomAD3 exomes AF: 0.367 AC: 92349 AN: 251384 Hom.: 17800 AF XY: 0.374 AC XY: 50747 AN XY: 135866

Gnomad AFR exome AF: 0.474

Gnomad AMR exome AF: 0.272

Gnomad ASJ exome AF: 0.403

Gnomad EAS exome AF: 0.417

Gnomad SAS exome AF: 0.486

Gnomad FIN exome AF: 0.320

Gnomad NFE exome AF: 0.348

Gnomad OTH exome AF: 0.356

GnomAD4 exome AF: 0.367 AC: 535955 AN: 1461772 Hom.: 100293 Cov.: 46 AF XY: 0.370 AC XY: 269176 AN XY: 727186

Gnomad4 AFR exome AF: 0.481

Gnomad4 AMR exome AF: 0.275

Gnomad4 ASJ exome AF: 0.405

Gnomad4 EAS exome AF: 0.396

Gnomad4 SAS exome AF: 0.478

Gnomad4 FIN exome AF: 0.311

Gnomad4 NFE exome AF: 0.358

Gnomad4 OTH exome AF: 0.379

GnomAD4 genome AF: 0.387 AC: 58788 AN: 152004 Hom.: 11709 Cov.: 32 AF XY: 0.384 AC XY: 28566 AN XY: 74306

Gnomad4 AFR AF: 0.468

Gnomad4 AMR AF: 0.296

Gnomad4 ASJ AF: 0.401

Gnomad4 EAS AF: 0.404

Gnomad4 SAS AF: 0.499

Gnomad4 FIN AF: 0.329

Gnomad4 NFE AF: 0.357

Gnomad4 OTH AF: 0.362

Alfa AF: 0.364 Hom.: 26505

Bravo AF: 0.387

TwinsUK AF: 0.354 AC: 1312

ALSPAC AF: 0.360 AC: 1388

ESP6500AA AF: 0.475 AC: 2092

ESP6500EA AF: 0.360 AC: 3094

ExAC AF: 0.374 AC: 45404

Asia WGS AF: 0.436 AC: 1517 AN: 3478

EpiCase AF: 0.356

EpiControl AF: 0.354

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.90	P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.084
Sift	Benign	0.069	T
Sift4G	Benign	0.077	T
Polyphen		0.62	P
Vest4		0.038
MPC		0.35
ClinPred		0.010	T
GERP RS		0.55
Varity_R		0.094
gMVP		0.33

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

Other links and lift over

dbSNP: rs1056892; hg19: chr21-37518706; COSMIC: COSV51740736; COSMIC: COSV51740736;