rs41557318

chr21-36071051-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001757.4(CBR1):c.391C>T(p.Pro131Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,604,806 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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 0.0021 (2 hom., cov: 30)
  • Exomes 𝑓: 0.0030 (12 hom.)
• Consequence: CBR1 NM_001757.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.01

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006199181).
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBR1	NM_001757.4	c.391C>T	p.Pro131Ser	missense_variant	2/3	ENST00000290349.11
CBR1-AS1	NR_040084.1	n.378-566G>A		intron_variant, non_coding_transcript_variant
CBR1	NM_001286789.2	c.391C>T	p.Pro131Ser	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBR1	ENST00000290349.11	c.391C>T	p.Pro131Ser	missense_variant	2/3	1	NM_001757.4	P1
CBR1-AS1	ENST00000535199.5	n.378-566G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00205 AC: 312 AN: 152018 Hom.: 2 Cov.: 30

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00293

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00368

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00248 AC: 623 AN: 251490 Hom.: 1 AF XY: 0.00271 AC XY: 369 AN XY: 135920

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00105

Gnomad FIN exome AF: 0.00259

Gnomad NFE exome AF: 0.00450

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00301 AC: 4367 AN: 1452670 Hom.: 12 Cov.: 29 AF XY: 0.00299 AC XY: 2163 AN XY: 723320

Gnomad4 AFR exome AF: 0.000240

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.0000767

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000918

Gnomad4 FIN exome AF: 0.00249

Gnomad4 NFE exome AF: 0.00361

Gnomad4 OTH exome AF: 0.00239

GnomAD4 genome AF: 0.00205 AC: 312 AN: 152136 Hom.: 2 Cov.: 30 AF XY: 0.00202 AC XY: 150 AN XY: 74386

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.000328

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.00293

Gnomad4 NFE AF: 0.00368

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00322 Hom.: 4

Bravo AF: 0.00167

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00325 AC: 394

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00284

EpiControl AF: 0.00243

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T;D;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0062	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.88	L;L;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-5.6	D;D;D;D
REVEL	Benign	0.23
Sift	Benign	0.11	T;T;T;D
Sift4G	Benign	0.18	T;T;T;T
Polyphen		0.014, 0.99	.;B;D;.
Vest4		0.46
MVP		0.28
MPC		0.38
ClinPred		0.035	T
GERP RS		5.6
Varity_R		0.57
gMVP		0.55

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: rs41557318; hg19: chr21-37443349; COSMIC: COSV51740212; COSMIC: COSV51740212;