8-27599962-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001831.4(CLU):c.982G>A(p.Asp328Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0022 in 1,614,130 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. D328D) has been classified as Benign.

Frequency

Genomes: 𝑓 0.010 ( 23 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 20 hom. )

Consequence

CLU
NM_001831.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.32

Publications

11 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026910007).

BP6

Variant 8-27599962-C-T is Benign according to our data. Variant chr8-27599962-C-T is described in ClinVar as Benign. ClinVar VariationId is 776303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0105 (1597/152262) while in subpopulation AFR AF = 0.0351 (1458/41546). AF 95% confidence interval is 0.0336. There are 23 homozygotes in GnomAd4. There are 775 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1597 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CLU	NM_001831.4 link	c.982G>A	p.Asp328Asn	missense_variant	Exon 7 of 9	ENST00000316403.15	NP_001822.3
CLU	NR_038335.2 link	n.1237G>A		non_coding_transcript_exon_variant	Exon 7 of 9
CLU	NR_045494.1 link	n.1162G>A		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.982G>A	p.Asp328Asn	missense_variant	Exon 7 of 9	1	NM_001831.4	ENSP00000315130.10

Frequencies

GnomAD3 genomes

AF:

0.0105

AC:

1597

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0352

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00432

Gnomad ASJ

AF:

0.00664

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.00329

AC:

828

AN:

251336

AF XY:

0.00241

show subpopulations

Gnomad AFR exome

AF:

0.0386

Gnomad AMR exome

AF:

0.00205

Gnomad ASJ exome

AF:

0.00804

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000246

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00134

AC:

1961

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

900

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.0334

AC:

1119

AN:

33480

American (AMR)

AF:

0.00250

AC:

112

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00811

AC:

212

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00416

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000287

AC:

319

AN:

1112004

Other (OTH)

AF:

0.00281

AC:

170

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

118

236

354

472

590

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<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:

0.0105

AC:

1597

AN:

152262

Hom.:

Cov.:

AF XY:

0.0104

AC XY:

775

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0351

AC:

1458

AN:

41546

American (AMR)

AF:

0.00432

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00664

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000323

AC:

AN:

68022

Other (OTH)

AF:

0.0118

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

158

237

316

395

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:

0.00338

Hom.:

Bravo

AF:

0.0117

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0377

AC:

166

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00397

AC:

482

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000237

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

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.70

CADD

Benign

9.4

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.17

T;T;T

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.52

.;.;T

MetaRNN

Benign

0.0027

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-2.1

N;N;N

PhyloP100

2.3

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.90

N;N;N

REVEL

Benign

0.094

Sift

Benign

0.49

T;T;T

Sift4G

Benign

0.68

T;T;T

Polyphen

0.0010

B;B;B

Vest4

0.039

MVP

0.25

MPC

0.46

ClinPred

0.0071

GERP RS

3.3

PromoterAI

-0.028

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.019

gMVP

0.33

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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