8-27604964-A-G

Variant names:

• chr8-27604964-A-G
• rs7982
• NM_001831.4:c.789T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_001831.4(CLU):​c.789T>C​(p.His263His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.611 in 1,613,754 control chromosomes in the GnomAD database, including 302,531 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.61 (28231 hom., cov: 31)
  • Exomes 𝑓: 0.61 (274300 hom.)
• Consequence: CLU NM_001831.4 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.467
• Publications: 62 publications found

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

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 8-27604964-A-G is Benign according to our data. Variant chr8-27604964-A-G is described in ClinVar as Benign. ClinVar VariationId is 3060904.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.467 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.768 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLU	NM_001831.4	c.789T>C	p.His263His	synonymous_variant	Exon 5 of 9	ENST00000316403.15	NP_001822.3
CLU	NR_038335.2	n.1044T>C		non_coding_transcript_exon_variant	Exon 5 of 9
CLU	NR_045494.1	n.969T>C		non_coding_transcript_exon_variant	Exon 5 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLU	ENST00000316403.15	c.789T>C	p.His263His	synonymous_variant	Exon 5 of 9	1	NM_001831.4	ENSP00000315130.10

Frequencies

GnomAD3 genomes AF: 0.608 AC: 92335 AN: 151818 Hom.: 28209 Cov.: 31

Gnomad AFR AF: 0.571

Gnomad AMI AF: 0.631

Gnomad AMR AF: 0.649

Gnomad ASJ AF: 0.590

Gnomad EAS AF: 0.788

Gnomad SAS AF: 0.705

Gnomad FIN AF: 0.597

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.603

Gnomad OTH AF: 0.616

GnomAD2 exomes AF: 0.636 AC: 160034 AN: 251456 AF XY: 0.638

Gnomad AFR exome AF: 0.573

Gnomad AMR exome AF: 0.677

Gnomad ASJ exome AF: 0.600

Gnomad EAS exome AF: 0.782

Gnomad FIN exome AF: 0.600

Gnomad NFE exome AF: 0.603

Gnomad OTH exome AF: 0.630

GnomAD4 exome AF: 0.611 AC: 893139 AN: 1461818 Hom.: 274300 Cov.: 63 AF XY: 0.614 AC XY: 446328 AN XY: 727214

African (AFR) AF: 0.569 AC: 19048 AN: 33478

American (AMR) AF: 0.670 AC: 29979 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.598 AC: 15638 AN: 26134

East Asian (EAS) AF: 0.763 AC: 30306 AN: 39700

South Asian (SAS) AF: 0.695 AC: 59951 AN: 86258

European-Finnish (FIN) AF: 0.594 AC: 31726 AN: 53416

Middle Eastern (MID) AF: 0.616 AC: 3554 AN: 5768

European-Non Finnish (NFE) AF: 0.599 AC: 665617 AN: 1111948

Other (OTH) AF: 0.618 AC: 37320 AN: 60392

GnomAD4 genome AF: 0.608 AC: 92411 AN: 151936 Hom.: 28231 Cov.: 31 AF XY: 0.612 AC XY: 45465 AN XY: 74254

African (AFR) AF: 0.571 AC: 23674 AN: 41442

American (AMR) AF: 0.649 AC: 9916 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.590 AC: 2045 AN: 3466

East Asian (EAS) AF: 0.788 AC: 4050 AN: 5140

South Asian (SAS) AF: 0.705 AC: 3389 AN: 4804

European-Finnish (FIN) AF: 0.597 AC: 6306 AN: 10558

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.603 AC: 40976 AN: 67952

Other (OTH) AF: 0.618 AC: 1299 AN: 2102

Alfa AF: 0.607 Hom.: 33993

Bravo AF: 0.612

Asia WGS AF: 0.726 AC: 2523 AN: 3478

EpiCase AF: 0.613

EpiControl AF: 0.606

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CLU-related disorder Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.39
DANN	Benign	0.39
PhyloP100		-0.47
PromoterAI		0.032	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7982; hg19: chr8-27462481; COSMIC: COSV57065941; COSMIC: COSV57065941;