Genetic Variant NM_001831.4:c.84C>T (chr8-27610488-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_001831.4(CLU):c.84C>T(p.Asp28Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,613,914 control chromosomes in the GnomAD database, including 1,541 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 0.055 ( 828 hom., cov: 33)

Exomes 𝑓: 0.0056 ( 713 hom. )

Consequence

CLU
NM_001831.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.907

Publications

4 publications found

Variant links:

Genes affected

CLU (HGNC:2095): (clusterin) The protein encoded by this gene is a secreted chaperone that can under some stress conditions also be found in the cell cytosol. It has been suggested to be involved in several basic biological events such as cell death, tumor progression, and neurodegenerative disorders. Alternate splicing results in both coding and non-coding variants.[provided by RefSeq, May 2011]

CLU links:

MIR6843 (HGNC:50240): (microRNA 6843) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR6843 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP7

Synonymous conserved (PhyloP=0.907 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLU	NM_001831.4 link	c.84C>T	p.Asp28Asp	synonymous_variant	Exon 2 of 9	ENST00000316403.15	NP_001822.3	P10909-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLU	ENST00000316403.15 link	c.84C>T	p.Asp28Asp	synonymous_variant	Exon 2 of 9	1	NM_001831.4	ENSP00000315130.10		P10909-1

Frequencies

GnomAD3 genomes

AF:

0.0551

AC:

8393

AN:

152208

Hom.:

828

Cov.:

show subpopulations

Gnomad AFR

AF:

0.191

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0202

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000720

Gnomad OTH

AF:

0.0406

GnomAD2 exomes

AF:

0.0140

AC:

3528

AN:

251438

AF XY:

0.0102

show subpopulations

Gnomad AFR exome

AF:

0.191

Gnomad AMR exome

AF:

0.00882

Gnomad ASJ exome

AF:

0.00218

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000501

Gnomad OTH exome

AF:

0.00603

GnomAD4 exome

AF:

0.00560

AC:

8184

AN:

1461588

Hom.:

713

Cov.:

AF XY:

0.00476

AC XY:

3460

AN XY:

727106

show subpopulations

African (AFR)

AF:

0.196

AC:

6543

AN:

33466

American (AMR)

AF:

0.00964

AC:

431

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00264

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000417

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00937

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000291

AC:

324

AN:

1111792

Other (OTH)

AF:

0.0120

AC:

727

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

366

731

1097

1462

1828

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

206

412

618

824

1030

<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:

0.0552

AC:

8408

AN:

152326

Hom.:

828

Cov.:

AF XY:

0.0526

AC XY:

3915

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.191

AC:

7947

AN:

41542

American (AMR)

AF:

0.0202

AC:

309

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5192

South Asian (SAS)

AF:

0.00103

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000720

AC:

AN:

68032

Other (OTH)

AF:

0.0402

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

354

708

1062

1416

1770

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

222

296

370

<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:

0.0259

Hom.:

187

Bravo

AF:

0.0628

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.000356

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

4.2

(source)

DANN

Benign

0.26

PhyloP100

0.91

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over