Genetic Variant NM_001831.4:c.*881T>C (chr8-27597360-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001831.4(CLU):c.*881T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0286 in 454,178 control chromosomes in the GnomAD database, including 304 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 0.028 ( 101 hom., cov: 32)

Exomes 𝑓: 0.029 ( 203 hom. )

Consequence

CLU
NM_001831.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.214

Publications

6 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:

ENSG00000300853 (HGNC:):

ENSG00000300853 links:

Genome browser will be placed here

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=-0.86).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0276 (4191/151954) while in subpopulation NFE AF = 0.0425 (2885/67926). AF 95% confidence interval is 0.0412. There are 101 homozygotes in GnomAd4. There are 2035 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 4191 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CLU	NM_001831.4 link	c.*881T>C	3_prime_UTR_variant	Exon 9 of 9	ENST00000316403.15	NP_001822.3	P10909-1
CLU	NR_038335.2 link	n.2486T>C	non_coding_transcript_exon_variant	Exon 9 of 9
CLU	NR_045494.1 link	n.2411T>C	non_coding_transcript_exon_variant	Exon 9 of 9
LOC124901919	XR_007060868.1 link	n.1691A>G	non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLU	ENST00000316403.15 link	c.*881T>C		3_prime_UTR_variant	Exon 9 of 9	1	NM_001831.4	ENSP00000315130.10		P10909-1

Frequencies

GnomAD3 genomes

AF:

0.0276

AC:

4192

AN:

151832

Hom.:

101

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00742

Gnomad AMI

AF:

0.0439

Gnomad AMR

AF:

0.0197

Gnomad ASJ

AF:

0.0173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00442

Gnomad FIN

AF:

0.0490

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0425

Gnomad OTH

AF:

0.0254

GnomAD2 exomes

AF:

0.0241

AC:

3290

AN:

136660

AF XY:

0.0237

show subpopulations

Gnomad AFR exome

AF:

0.00544

Gnomad AMR exome

AF:

0.0163

Gnomad ASJ exome

AF:

0.0140

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0494

Gnomad NFE exome

AF:

0.0411

Gnomad OTH exome

AF:

0.0290

GnomAD4 exome

AF:

0.0291

AC:

8794

AN:

302224

Hom.:

203

Cov.:

AF XY:

0.0266

AC XY:

4589

AN XY:

172254

show subpopulations

African (AFR)

AF:

0.00713

AC:

AN:

8554

American (AMR)

AF:

0.0165

AC:

450

AN:

27274

Ashkenazi Jewish (ASJ)

AF:

0.0146

AC:

158

AN:

10786

East Asian (EAS)

AF:

0.00

AC:

AN:

9210

South Asian (SAS)

AF:

0.00484

AC:

289

AN:

59650

European-Finnish (FIN)

AF:

0.0465

AC:

595

AN:

12790

Middle Eastern (MID)

AF:

0.0122

AC:

AN:

1150

European-Non Finnish (NFE)

AF:

0.0428

AC:

6801

AN:

158764

Other (OTH)

AF:

0.0303

AC:

426

AN:

14046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

719

1438

2158

2877

3596

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.0276

AC:

4191

AN:

151954

Hom.:

101

Cov.:

AF XY:

0.0274

AC XY:

2035

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.00740

AC:

307

AN:

41502

American (AMR)

AF:

0.0197

AC:

301

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.0173

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5112

South Asian (SAS)

AF:

0.00464

AC:

AN:

4746

European-Finnish (FIN)

AF:

0.0490

AC:

520

AN:

10614

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0425

AC:

2885

AN:

67926

Other (OTH)

AF:

0.0251

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

218

435

653

870

1088

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<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:

0.0354

Hom.:

314

Bravo

AF:

0.0246

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.88

(source)

DANN

Benign

0.69

PhyloP100

-0.21

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