NM_001144757.3:c.88C>T

Variant names:

• chr15-32643680-C-T
• rs532967380
• NM_001144757.3:c.88C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001144757.3(SCG5):​c.88C>T​(p.Arg30Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: SCG5 NM_001144757.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.892
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3243333).

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.88C>T	p.Arg30Trp	missense	Exon 2 of 6	NP_001138229.1	P05408-1
	ARHGAP11A-SCG5	NM_001368319.1		c.1330C>T	p.Arg444Trp	missense	Exon 10 of 14	NP_001355248.1	A0A8I5KWH8
	SCG5	NM_003020.5		c.88C>T	p.Arg30Trp	missense	Exon 2 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.88C>T	p.Arg30Trp	missense	Exon 2 of 6	ENSP00000300175.4	P05408-1
	ARHGAP11A-SCG5	ENST00000692248.1		c.1330C>T	p.Arg444Trp	missense	Exon 10 of 14	ENSP00000510771.1	A0A8I5KWH8
	SCG5	ENST00000413748.6	TSL:1	c.88C>T	p.Arg30Trp	missense	Exon 2 of 6	ENSP00000388560.2	P05408-2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152066 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000441 AC: 11 AN: 249256 AF XY: 0.0000444

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461690 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 727132

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111854

Other (OTH) AF: 0.0000166 AC: 1 AN: 60372

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74406

African (AFR) AF: 0.0000241 AC: 1 AN: 41488

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000497 AC: 6

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.66	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.89
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.28
Sift	Benign	0.030	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.26	B
Vest4		0.83
MutPred		0.75		Loss of disorder (P = 0.0118)
MVP		0.34
MPC		0.098
ClinPred		0.094	T
GERP RS		1.8
PromoterAI		0.018	Neutral
Varity_R		0.13
gMVP		0.85
Mutation Taster		=69/31	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: rs532967380; hg19: chr15-32935881;