21-36071051-C-T

Variant names:

• chr21-36071051-C-T
• rs41557318
• NM_001757.4:c.391C>T

Variant summary

Our verdict is Benign. The variant received -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. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 15 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006199181).
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001757.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBR1	NM_001757.4	MANE Select	c.391C>T	p.Pro131Ser	missense	Exon 2 of 3	NP_001748.1
	CBR1	NM_001286789.2		c.391C>T	p.Pro131Ser	missense	Exon 2 of 3	NP_001273718.1
	CBR1-AS1	NR_040084.1		n.378-566G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBR1	ENST00000290349.11	TSL:1 MANE Select	c.391C>T	p.Pro131Ser	missense	Exon 2 of 3	ENSP00000290349.6
	CBR1	ENST00000439427.2	TSL:1	c.391C>T	p.Pro131Ser	missense	Exon 2 of 2	ENSP00000395132.2
	CBR1	ENST00000530908.5	TSL:1	c.391C>T	p.Pro131Ser	missense	Exon 2 of 3	ENSP00000434613.1

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

GnomAD2 exomes AF: 0.00248 AC: 623 AN: 251490 AF XY: 0.00271

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 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

African (AFR) AF: 0.000240 AC: 8 AN: 33292

American (AMR) AF: 0.000268 AC: 12 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0000767 AC: 2 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.000918 AC: 79 AN: 86082

European-Finnish (FIN) AF: 0.00249 AC: 133 AN: 53414

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5748

European-Non Finnish (NFE) AF: 0.00361 AC: 3983 AN: 1103580

Other (OTH) AF: 0.00239 AC: 144 AN: 60126

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

African (AFR) AF: 0.000433 AC: 18 AN: 41524

American (AMR) AF: 0.000328 AC: 5 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4816

European-Finnish (FIN) AF: 0.00293 AC: 31 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00368 AC: 250 AN: 67976

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00320 Hom.: 5

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 v4.9

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
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.88	L
PhyloP100		3.0
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Benign	0.23
Sift	Benign	0.11	T
Sift4G	Benign	0.18	T
Polyphen		0.014	B
Vest4		0.46
MVP		0.28
MPC		0.38
ClinPred		0.035	T
GERP RS		5.6
Varity_R		0.57
gMVP		0.55
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

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