15-32684662-G-C

Variant names:

• chr15-32684662-G-C
• rs200135028
• NM_001144757.3:c.482G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001144757.3(SCG5):​c.482G>C​(p.Gly161Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,798 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G161V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SCG5 NM_001144757.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.93
• Publications: 1 publications found

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]

ARHGAP11A-SCG5 (HGNC:56310): (ARHGAP11A-SCG5 readthrough) This locus represents naturally occurring readthrough transcription between the neighboring ARHGAP11A (Rho GTPase activating protein 11A) and SCG5 (secretogranin V) genes on chromosome 15q13.3. The readthrough transcript encodes a fusion protein that shares sequence identity with both the ARHGAP11A and SCG5 gene products. [provided by RefSeq, Feb 2019]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18991074).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001144757.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCG5	NM_001144757.3	MANE Select	c.482G>C	p.Gly161Ala	missense	Exon 4 of 6	NP_001138229.1	P05408-1
	ARHGAP11A-SCG5	NM_001368319.1		c.1721G>C	p.Gly574Ala	missense	Exon 12 of 14	NP_001355248.1	A0A8I5KWH8
	SCG5	NM_003020.5		c.479G>C	p.Gly160Ala	missense	Exon 4 of 6	NP_003011.1	P05408-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCG5	ENST00000300175.9	TSL:1 MANE Select	c.482G>C	p.Gly161Ala	missense	Exon 4 of 6	ENSP00000300175.4	P05408-1
	ARHGAP11A-SCG5	ENST00000692248.1		c.1721G>C	p.Gly574Ala	missense	Exon 12 of 14	ENSP00000510771.1	A0A8I5KWH8
	SCG5	ENST00000413748.6	TSL:1	c.479G>C	p.Gly160Ala	missense	Exon 4 of 6	ENSP00000388560.2	P05408-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 247582 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457798 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 725312

African (AFR) AF: 0.00 AC: 0 AN: 33416

American (AMR) AF: 0.00 AC: 0 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 85846

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108704

Other (OTH) AF: 0.00 AC: 0 AN: 60270

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.48	N
PhyloP100		4.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.029
Sift	Benign	0.25	T
Sift4G	Benign	0.27	T
Polyphen		0.0050	B
Vest4		0.30
MutPred		0.40		Gain of helix (P = 0.0425)
MVP		0.45
MPC		0.077
ClinPred		0.75	D
GERP RS		5.7
Varity_R		0.12
gMVP		0.32
Mutation Taster		=62/38	polymorphism

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: rs200135028; hg19: chr15-32976863;