Genetic Variant CLU:c.246+140A>G (chr8-27608798-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001831.4(CLU):c.246+140A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.641 in 878,274 control chromosomes in the GnomAD database, including 182,103 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 0.68 ( 35540 hom., cov: 34)

Exomes 𝑓: 0.63 ( 146563 hom. )

Consequence

CLU
NM_001831.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.418

Publications

89 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.803 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001831.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CLU	NM_001831.4	MANE Select	c.246+140A>G	intron	N/A	NP_001822.3
CLU	NR_038335.2		n.501+140A>G	intron	N/A
CLU	NR_045494.1		n.426+140A>G	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CLU	ENST00000316403.15	TSL:1 MANE Select	c.246+140A>G	intron	N/A	ENSP00000315130.10
CLU	ENST00000405140.7	TSL:1	c.246+140A>G	intron	N/A	ENSP00000385419.3
CLU	ENST00000523500.5	TSL:1	c.246+140A>G	intron	N/A	ENSP00000429620.1

Frequencies

GnomAD3 genomes

AF:

0.678

AC:

103068

AN:

152074

Hom.:

35497

Cov.:

show subpopulations

Gnomad AFR

AF:

0.810

Gnomad AMI

AF:

0.629

Gnomad AMR

AF:

0.676

Gnomad ASJ

AF:

0.592

Gnomad EAS

AF:

0.776

Gnomad SAS

AF:

0.705

Gnomad FIN

AF:

0.595

Gnomad MID

AF:

0.630

Gnomad NFE

AF:

0.607

Gnomad OTH

AF:

0.668

GnomAD4 exome

AF:

0.633

AC:

459905

AN:

726082

Hom.:

146563

Cov.:

AF XY:

0.635

AC XY:

245649

AN XY:

386870

show subpopulations

African (AFR)

AF:

0.807

AC:

15506

AN:

19210

American (AMR)

AF:

0.683

AC:

28150

AN:

41216

Ashkenazi Jewish (ASJ)

AF:

0.603

AC:

12556

AN:

20818

East Asian (EAS)

AF:

0.740

AC:

26880

AN:

36302

South Asian (SAS)

AF:

0.696

AC:

48217

AN:

69314

European-Finnish (FIN)

AF:

0.591

AC:

25116

AN:

42522

Middle Eastern (MID)

AF:

0.637

AC:

1972

AN:

3096

European-Non Finnish (NFE)

AF:

0.609

AC:

278283

AN:

457326

Other (OTH)

AF:

0.640

AC:

23225

AN:

36278

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

9328

18657

27985

37314

46642

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3866

7732

11598

15464

19330

<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:

0.678

AC:

103169

AN:

152192

Hom.:

35540

Cov.:

AF XY:

0.678

AC XY:

50468

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.810

AC:

33644

AN:

41536

American (AMR)

AF:

0.676

AC:

10330

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.592

AC:

2055

AN:

3472

East Asian (EAS)

AF:

0.776

AC:

4016

AN:

5176

South Asian (SAS)

AF:

0.705

AC:

3398

AN:

4822

European-Finnish (FIN)

AF:

0.595

AC:

6304

AN:

10594

Middle Eastern (MID)

AF:

0.626

AC:

184

AN:

294

European-Non Finnish (NFE)

AF:

0.607

AC:

41250

AN:

67986

Other (OTH)

AF:

0.670

AC:

1416

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1696

3392

5087

6783

8479

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

812

1624

2436

3248

4060

<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:

0.636

Hom.:

116498

Bravo

AF:

0.691

Asia WGS

AF:

0.734

AC:

2551

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

5.9

(source)

DANN

Benign

0.58

PhyloP100

-0.42

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over