Genetic Variant NM_001831.4:c.246+274A>G (chr8-27608664-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+274A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.652 in 564,874 control chromosomes in the GnomAD database, including 122,713 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 0.70 ( 38229 hom., cov: 34)

Exomes 𝑓: 0.64 ( 84484 hom. )

Consequence

CLU
NM_001831.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.765

Publications

16 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=-0.91).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.878 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+274A>G	intron	N/A	NP_001822.3
CLU	NR_038335.2		n.501+274A>G	intron	N/A
CLU	NR_045494.1		n.426+274A>G	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CLU	ENST00000316403.15	TSL:1 MANE Select	c.246+274A>G	intron	N/A	ENSP00000315130.10
CLU	ENST00000405140.7	TSL:1	c.246+274A>G	intron	N/A	ENSP00000385419.3
CLU	ENST00000523500.5	TSL:1	c.246+274A>G	intron	N/A	ENSP00000429620.1

Frequencies

GnomAD3 genomes

AF:

0.698

AC:

106184

AN:

152080

Hom.:

38174

Cov.:

show subpopulations

Gnomad AFR

AF:

0.886

Gnomad AMI

AF:

0.628

Gnomad AMR

AF:

0.683

Gnomad ASJ

AF:

0.592

Gnomad EAS

AF:

0.787

Gnomad SAS

AF:

0.708

Gnomad FIN

AF:

0.593

Gnomad MID

AF:

0.630

Gnomad NFE

AF:

0.603

Gnomad OTH

AF:

0.687

GnomAD4 exome

AF:

0.636

AC:

262257

AN:

412676

Hom.:

84484

Cov.:

AF XY:

0.638

AC XY:

139029

AN XY:

217966

show subpopulations

African (AFR)

AF:

0.882

AC:

10250

AN:

11624

American (AMR)

AF:

0.679

AC:

11784

AN:

17360

Ashkenazi Jewish (ASJ)

AF:

0.599

AC:

7482

AN:

12488

East Asian (EAS)

AF:

0.762

AC:

21152

AN:

27764

South Asian (SAS)

AF:

0.697

AC:

30774

AN:

44178

European-Finnish (FIN)

AF:

0.585

AC:

15598

AN:

26676

Middle Eastern (MID)

AF:

0.639

AC:

1161

AN:

1816

European-Non Finnish (NFE)

AF:

0.602

AC:

148767

AN:

247074

Other (OTH)

AF:

0.645

AC:

15289

AN:

23696

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

4550

9100

13649

18199

22749

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

748

1496

2244

2992

3740

<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:

0.698

AC:

106298

AN:

152198

Hom.:

38229

Cov.:

AF XY:

0.698

AC XY:

51948

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.886

AC:

36820

AN:

41554

American (AMR)

AF:

0.683

AC:

10443

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.592

AC:

2055

AN:

3472

East Asian (EAS)

AF:

0.787

AC:

4068

AN:

5172

South Asian (SAS)

AF:

0.708

AC:

3415

AN:

4826

European-Finnish (FIN)

AF:

0.593

AC:

6276

AN:

10580

Middle Eastern (MID)

AF:

0.626

AC:

184

AN:

294

European-Non Finnish (NFE)

AF:

0.603

AC:

41013

AN:

67982

Other (OTH)

AF:

0.688

AC:

1451

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1576

3152

4729

6305

7881

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

818

1636

2454

3272

4090

<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:

0.697

Hom.:

5633

Bravo

AF:

0.716

Asia WGS

AF:

0.744

AC:

2585

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

2.8

(source)

DANN

Benign

0.41

PhyloP100

-0.77

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