Genetic Variant CBR1:p.Val231Val (chr21-36072741-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP7BS1BS2

The NM_001757.4(CBR1):c.693G>A(p.Val231Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0126 in 1,614,130 control chromosomes in the GnomAD database, including 176 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.016 ( 22 hom., cov: 31)

Exomes 𝑓: 0.012 ( 154 hom. )

Consequence

CBR1
NM_001757.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.368

Publications

3 publications found

Variant links:

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]

CBR1 links:

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]

SETD4 links:

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

CBR1-AS1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001757.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP7

Synonymous conserved (PhyloP=0.368 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0165 (2506/152246) while in subpopulation AMR AF = 0.024 (367/15294). AF 95% confidence interval is 0.022. There are 22 homozygotes in GnomAd4. There are 1207 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 22 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CBR1	NM_001757.4	MANE Select	c.693G>A	p.Val231Val	synonymous	Exon 3 of 3	NP_001748.1	P16152-1
CBR1	NM_001286789.2		c.*802G>A		3_prime_UTR	Exon 3 of 3	NP_001273718.1	P16152-2
CBR1-AS1	NR_040084.1		n.377+2140C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CBR1	ENST00000290349.11	TSL:1 MANE Select	c.693G>A	p.Val231Val	synonymous	Exon 3 of 3	ENSP00000290349.6	P16152-1
CBR1	ENST00000530908.5	TSL:1	c.*802G>A		3_prime_UTR	Exon 3 of 3	ENSP00000434613.1	P16152-2
SETD4	ENST00000399201.5	TSL:1	c.-203+6564C>T		intron	N/A	ENSP00000382152.1	A8MTS1

Frequencies

GnomAD3 genomes

AF:

0.0165

AC:

2509

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0209

Gnomad AMI

AF:

0.0526

Gnomad AMR

AF:

0.0240

Gnomad ASJ

AF:

0.0219

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.0172

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0130

Gnomad OTH

AF:

0.0316

GnomAD2 exomes

AF:

0.0129

AC:

3215

AN:

249818

AF XY:

0.0122

show subpopulations

Gnomad AFR exome

AF:

0.0201

Gnomad AMR exome

AF:

0.0172

Gnomad ASJ exome

AF:

0.0239

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0187

Gnomad NFE exome

AF:

0.0131

Gnomad OTH exome

AF:

0.0178

GnomAD4 exome

AF:

0.0122

AC:

17835

AN:

1461884

Hom.:

154

Cov.:

AF XY:

0.0121

AC XY:

8771

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.0215

AC:

720

AN:

33480

American (AMR)

AF:

0.0186

AC:

830

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0219

AC:

573

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00303

AC:

261

AN:

86258

European-Finnish (FIN)

AF:

0.0191

AC:

1019

AN:

53418

Middle Eastern (MID)

AF:

0.0277

AC:

160

AN:

5768

European-Non Finnish (NFE)

AF:

0.0119

AC:

13281

AN:

1112006

Other (OTH)

AF:

0.0164

AC:

991

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

1010

2019

3029

4038

5048

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

508

1016

1524

2032

2540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0165

AC:

2506

AN:

152246

Hom.:

Cov.:

AF XY:

0.0162

AC XY:

1207

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0207

AC:

861

AN:

41544

American (AMR)

AF:

0.0240

AC:

367

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0219

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0172

AC:

182

AN:

10612

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0130

AC:

883

AN:

68018

Other (OTH)

AF:

0.0313

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

121

243

364

486

607

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0146

Hom.:

Bravo

AF:

0.0178

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0147

EpiControl

AF:

0.0141

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

5.9

(source)

DANN

Benign

0.80

PhyloP100

0.37

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over