8-27599990-G-C

Variant names:

• chr8-27599990-G-C
• rs9331937
• NM_001831.4:c.954C>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001831.4(CLU):​c.954C>G​(p.Pro318Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00489 in 1,614,098 control chromosomes in the GnomAD database, including 361 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (183 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (178 hom.)
• Consequence: CLU NM_001831.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.66
• Publications: 5 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.176).
• BP6: Variant 8-27599990-G-C is Benign according to our data. Variant chr8-27599990-G-C is described in ClinVar as Benign. ClinVar VariationId is 776304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.66 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0878 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001831.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLU	NM_001831.4	MANE Select	c.954C>G	p.Pro318Pro	synonymous	Exon 7 of 9	NP_001822.3
	CLU	NR_038335.2		n.1209C>G		non_coding_transcript_exon	Exon 7 of 9
	CLU	NR_045494.1		n.1134C>G		non_coding_transcript_exon	Exon 7 of 9

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLU	ENST00000316403.15	TSL:1 MANE Select	c.954C>G	p.Pro318Pro	synonymous	Exon 7 of 9	ENSP00000315130.10
	CLU	ENST00000405140.7	TSL:1	c.954C>G	p.Pro318Pro	synonymous	Exon 7 of 9	ENSP00000385419.3
	CLU	ENST00000523500.5	TSL:1	c.954C>G	p.Pro318Pro	synonymous	Exon 6 of 8	ENSP00000429620.1

Frequencies

GnomAD3 genomes AF: 0.0259 AC: 3939 AN: 152164 Hom.: 182 Cov.: 32

Gnomad AFR AF: 0.0902

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00909

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0225

GnomAD2 exomes AF: 0.00719 AC: 1808 AN: 251360 AF XY: 0.00518

Gnomad AFR exome AF: 0.0975

Gnomad AMR exome AF: 0.00520

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00270 AC: 3950 AN: 1461816 Hom.: 178 Cov.: 31 AF XY: 0.00231 AC XY: 1681 AN XY: 727220

African (AFR) AF: 0.0942 AC: 3153 AN: 33470

American (AMR) AF: 0.00566 AC: 253 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000348 AC: 30 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5768

European-Non Finnish (NFE) AF: 0.0000854 AC: 95 AN: 1111978

Other (OTH) AF: 0.00656 AC: 396 AN: 60386

GnomAD4 genome AF: 0.0259 AC: 3950 AN: 152282 Hom.: 183 Cov.: 32 AF XY: 0.0251 AC XY: 1872 AN XY: 74472

African (AFR) AF: 0.0902 AC: 3745 AN: 41520

American (AMR) AF: 0.00908 AC: 139 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68036

Other (OTH) AF: 0.0223 AC: 47 AN: 2108

Alfa AF: 0.00747 Hom.: 15

Bravo AF: 0.0302

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.10
DANN	Benign	0.49
PhyloP100		-3.7
PromoterAI		-0.044	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: rs9331937; hg19: chr8-27457507;