8-27599962-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. 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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.32

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]

ACMG classification

Verdict is Benign. Variant got -14 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 id is 776303.Status of the report is criteria_provided_single_submitter, 1 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1597 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLU	NM_001831.4	c.982G>A	p.Asp328Asn	missense_variant	7/9	ENST00000316403.15
CLU	NR_038335.2	n.1237G>A		non_coding_transcript_exon_variant	7/9
CLU	NR_045494.1	n.1162G>A		non_coding_transcript_exon_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLU	ENST00000316403.15	c.982G>A	p.Asp328Asn	missense_variant	7/9	1	NM_001831.4	P1

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1597 AN: 152144 Hom.: 23 Cov.: 32

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

GnomAD3 exomes AF: 0.00329 AC: 828 AN: 251336 Hom.: 12 AF XY: 0.00241 AC XY: 328 AN XY: 135874

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 SAS exome AF: 0.00

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.: 20 Cov.: 31 AF XY: 0.00124 AC XY: 900 AN XY: 727238

Gnomad4 AFR exome AF: 0.0334

Gnomad4 AMR exome AF: 0.00250

Gnomad4 ASJ exome AF: 0.00811

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000287

Gnomad4 OTH exome AF: 0.00281

GnomAD4 genome AF: 0.0105 AC: 1597 AN: 152262 Hom.: 23 Cov.: 32 AF XY: 0.0104 AC XY: 775 AN XY: 74464

Gnomad4 AFR AF: 0.0351

Gnomad4 AMR AF: 0.00432

Gnomad4 ASJ AF: 0.00664

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00275 Hom.: 6

Bravo AF: 0.0117

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0377 AC: 166

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00397 AC: 482

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	9.4
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	N
MetaRNN	Benign	0.0027	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.1	N;N;N
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.31	T
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	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.019
gMVP		0.33

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

LitVar

Other links and lift over

dbSNP: rs9331938; hg19: chr8-27457479; COSMIC: COSV57066559; COSMIC: COSV57066559;