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GeneBe

15-32643603-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001144757.3(SCG5):c.11G>A(p.Arg4Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,613,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

SCG5
NM_001144757.3 missense

Scores

18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0840
Variant links:
Genes affected
SCG5 (HGNC:10816): (secretogranin V) This gene encodes a secreted chaperone protein that prevents the aggregation of other secreted proteins, including proteins that are associated with neurodegenerative and metabolic disease. The encoded protein may be best known for its role in the trafficking and activation of prohormone convertase PC2 (encoded by Gene ID: 5126). Phosphorylation of the encoded protein has been shown to have an inhibitory effect on its chaperone function. This gene also produces a ARHGAP11A-SCG5 readthrough transcript and ARHGAP11A-SCG5 protein. [provided by RefSeq, Feb 2019]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.03774801).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SCG5NM_001144757.3 linkuse as main transcriptc.11G>A p.Arg4Lys missense_variant 2/6 ENST00000300175.9
ARHGAP11A-SCG5NM_001368319.1 linkuse as main transcriptc.1253G>A p.Arg418Lys missense_variant 10/14

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SCG5ENST00000300175.9 linkuse as main transcriptc.11G>A p.Arg4Lys missense_variant 2/61 NM_001144757.3 P1P05408-1

Frequencies

GnomAD3 genomes
AF:
0.000204
AC:
31
AN:
152128
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000321
AC:
8
AN:
249232
Hom.:
0
AF XY:
0.0000296
AC XY:
4
AN XY:
135206
show subpopulations
Gnomad AFR exome
AF:
0.000452
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000885
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000253
AC:
37
AN:
1461428
Hom.:
0
Cov.:
32
AF XY:
0.0000193
AC XY:
14
AN XY:
726966
show subpopulations
Gnomad4 AFR exome
AF:
0.00105
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.000204
AC:
31
AN:
152128
Hom.:
0
Cov.:
32
AF XY:
0.000148
AC XY:
11
AN XY:
74312
show subpopulations
Gnomad4 AFR
AF:
0.000724
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000322
Hom.:
0
Bravo
AF:
0.000234
ExAC
AF:
0.0000248
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 07, 2021The c.11G>A (p.R4K) alteration is located in exon 2 (coding exon 1) of the SCG5 gene. This alteration results from a G to A substitution at nucleotide position 11, causing the arginine (R) at amino acid position 4 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.083
BayesDel_addAF
Benign
-0.48
T
BayesDel_noAF
Benign
-0.56
Cadd
Benign
11
Dann
Benign
0.84
DEOGEN2
Benign
0.16
T;.;.;T
Eigen
Benign
-0.85
Eigen_PC
Benign
-0.82
FATHMM_MKL
Benign
0.14
N
M_CAP
Benign
0.0031
T
MetaRNN
Benign
0.038
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.0
L;L;.;.
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.29
T
PROVEAN
Benign
-0.38
N;N;N;N
REVEL
Benign
0.039
Sift
Benign
0.23
T;T;T;T
Sift4G
Benign
0.82
T;T;T;T
Polyphen
0.0010
B;.;.;.
Vest4
0.24
MVP
0.29
MPC
0.067
ClinPred
0.013
T
GERP RS
0.95
Varity_R
0.059
gMVP
0.49

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs772090948; hg19: chr15-32935804; API