21-36072553-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001757.4(CBR1):c.505G>C(p.Val169Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000387 in 1,601,072 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: CBR1 NM_001757.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.78

Genes affected

CBR1 (HGNC:1548): (carbonyl reductase 1) The protein encoded by this gene belongs to the short-chain dehydrogenases/reductases (SDR) family, which function as NADPH-dependent oxidoreductases having wide specificity for carbonyl compounds, such as quinones, prostaglandins, and various xenobiotics. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Nov 2013]

SETD4 (HGNC:1258): (SET domain containing 4) Enables histone methyltransferase activity (H4-K20 specific). Involved in histone H4-K20 trimethylation. Located in cytosol and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

CBR1-AS1 (HGNC:55777): (CBR1 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.115828365).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBR1	NM_001757.4	c.505G>C	p.Val169Leu	missense_variant	3/3	ENST00000290349.11
CBR1-AS1	NR_040084.1	n.378-2068C>G		intron_variant, non_coding_transcript_variant
CBR1	NM_001286789.2	c.*614G>C		3_prime_UTR_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBR1	ENST00000290349.11	c.505G>C	p.Val169Leu	missense_variant	3/3	1	NM_001757.4	P1
CBR1-AS1	ENST00000535199.5	n.378-2068C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000707 AC: 17 AN: 240612 Hom.: 0 AF XY: 0.0000845 AC XY: 11 AN XY: 130172

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000624

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000210

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000728

Gnomad OTH exome AF: 0.000174

GnomAD4 exome AF: 0.0000393 AC: 57 AN: 1448784 Hom.: 0 Cov.: 33 AF XY: 0.0000347 AC XY: 25 AN XY: 719864

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000952

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000945

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000217

Gnomad4 OTH exome AF: 0.0000335

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74474

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000904 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000824 AC: 10

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2024

The c.505G>C (p.V169L) alteration is located in exon 3 (coding exon 3) of the CBR1 gene. This alteration results from a G to C substitution at nucleotide position 505, causing the valine (V) at amino acid position 169 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	0.071
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.061
Sift	Benign	0.071	T
Sift4G	Benign	0.29	T
Polyphen		0.025	B
Vest4		0.36
MutPred		0.38		Loss of helix (P = 0.0444);
MVP		0.12
MPC		0.27
ClinPred		0.055	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.37
gMVP		0.67

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: rs557925178; hg19: chr21-37444851;