dbSNP rs9331939: CLU:p.Asp328Asp (chr8-27599960-G-A) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001831.4(CLU):c.984C>T(p.Asp328Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00971 in 1,614,184 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0061 ( 4 hom., cov: 32)

Exomes 𝑓: 0.010 ( 108 hom. )

Consequence

CLU
NM_001831.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.204

Publications

8 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.047).

BP6

Variant 8-27599960-G-A is Benign according to our data. Variant chr8-27599960-G-A is described in ClinVar as Benign. ClinVar VariationId is 788866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.204 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00607 (924/152312) while in subpopulation SAS AF = 0.0228 (110/4826). AF 95% confidence interval is 0.0193. There are 4 homozygotes in GnomAd4. There are 459 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 924 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLU	NM_001831.4 link	c.984C>T	p.Asp328Asp	synonymous_variant	Exon 7 of 9	ENST00000316403.15	NP_001822.3	P10909-1
CLU	NR_038335.2 link	n.1239C>T		non_coding_transcript_exon_variant	Exon 7 of 9
CLU	NR_045494.1 link	n.1164C>T		non_coding_transcript_exon_variant	Exon 7 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLU	ENST00000316403.15 link	c.984C>T	p.Asp328Asp	synonymous_variant	Exon 7 of 9	1	NM_001831.4	ENSP00000315130.10		P10909-1

Frequencies

GnomAD3 genomes

AF:

0.00607

AC:

924

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00174

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00380

Gnomad ASJ

AF:

0.0323

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0228

Gnomad FIN

AF:

0.00377

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00766

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00901

AC:

2264

AN:

251386

AF XY:

0.00998

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.00237

Gnomad ASJ exome

AF:

0.0328

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00319

Gnomad NFE exome

AF:

0.00908

Gnomad OTH exome

AF:

0.00978

GnomAD4 exome

AF:

0.0101

AC:

14748

AN:

1461872

Hom.:

108

Cov.:

AF XY:

0.0105

AC XY:

7604

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00164

AC:

AN:

33480

American (AMR)

AF:

0.00257

AC:

115

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0339

AC:

885

AN:

26134

East Asian (EAS)

AF:

0.000151

AC:

AN:

39698

South Asian (SAS)

AF:

0.0224

AC:

1929

AN:

86258

European-Finnish (FIN)

AF:

0.00401

AC:

214

AN:

53414

Middle Eastern (MID)

AF:

0.00971

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00977

AC:

10869

AN:

1112000

Other (OTH)

AF:

0.0102

AC:

619

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

847

1694

2541

3388

4235

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

460

920

1380

1840

2300

<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:

0.00607

AC:

924

AN:

152312

Hom.:

Cov.:

AF XY:

0.00616

AC XY:

459

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00173

AC:

AN:

41568

American (AMR)

AF:

0.00379

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0323

AC:

112

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.0228

AC:

110

AN:

4826

European-Finnish (FIN)

AF:

0.00377

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00766

AC:

521

AN:

68028

Other (OTH)

AF:

0.00427

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

140

186

233

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00948

Hom.:

Bravo

AF:

0.00567

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.00905

EpiControl

AF:

0.00895

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

3.5

(source)

DANN

Benign

0.36

PhyloP100

0.20

PromoterAI

-0.059

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over