8-27610488-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_ModerateBS2

The NM_001831.4(CLU):​c.84C>G​(p.Asp28Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000034 ( 0 hom. )

Consequence

CLU
NM_001831.4 missense

Scores

19

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.907
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]
MIR6843 (HGNC:50240): (microRNA 6843) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.09484419).
BS2
High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CLUNM_001831.4 linkc.84C>G p.Asp28Glu missense_variant Exon 2 of 9 ENST00000316403.15 NP_001822.3 P10909-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CLUENST00000316403.15 linkc.84C>G p.Asp28Glu missense_variant Exon 2 of 9 1 NM_001831.4 ENSP00000315130.10 P10909-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461602
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727110
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.59
CADD
Benign
3.3
DANN
Benign
0.87
DEOGEN2
Benign
0.12
T;T;T;T;T;T;T;T;.;.;.;T
Eigen
Benign
-0.75
Eigen_PC
Benign
-0.84
FATHMM_MKL
Benign
0.096
N
LIST_S2
Benign
0.45
.;.;T;T;T;T;T;T;T;.;T;T
M_CAP
Benign
0.0073
T
MetaRNN
Benign
0.095
T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.6
L;L;L;.;.;.;.;.;.;.;.;.
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-0.15
N;N;N;N;N;N;N;N;N;N;N;D
REVEL
Benign
0.043
Sift
Benign
0.28
T;T;T;T;T;T;T;T;T;T;T;.
Sift4G
Benign
0.49
T;T;T;T;.;T;T;.;.;.;.;D
Polyphen
0.24
B;B;B;.;.;.;.;.;.;.;.;.
Vest4
0.059
MutPred
0.51
Gain of disorder (P = 0.1512);Gain of disorder (P = 0.1512);Gain of disorder (P = 0.1512);Gain of disorder (P = 0.1512);.;Gain of disorder (P = 0.1512);Gain of disorder (P = 0.1512);Gain of disorder (P = 0.1512);Gain of disorder (P = 0.1512);Gain of disorder (P = 0.1512);Gain of disorder (P = 0.1512);Gain of disorder (P = 0.1512);
MVP
0.29
MPC
0.45
ClinPred
0.22
T
GERP RS
2.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.024
gMVP
0.22

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-27468005; API