Genetic Variant SCG2:p.Trp8Cys (chr2-223599259-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003469.5(SCG2):c.24G>T(p.Trp8Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000279 in 1,434,890 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

SCG2
NM_003469.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.00100

Variant links:

Genes affected

SCG2 (HGNC:10575): (secretogranin II) The protein encoded by this gene is a member of the chromogranin/secretogranin family of neuroendocrine secretory proteins. Studies in rodents suggest that the full-length protein, secretogranin II, is involved in the packaging or sorting of peptide hormones and neuropeptides into secretory vesicles. The full-length protein is cleaved to produce the active peptide secretoneurin, which exerts chemotaxic effects on specific cell types, and EM66, whose function is unknown. [provided by RefSeq, Jul 2008]

SCG2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16285858).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCG2	NM_003469.5 link	c.24G>T	p.Trp8Cys	missense_variant	Exon 2 of 2	ENST00000305409.3	NP_003460.2	P13521

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCG2	ENST00000305409.3 link	c.24G>T	p.Trp8Cys	missense_variant	Exon 2 of 2	1	NM_003469.5	ENSP00000304133.2	P13521
SCG2	ENST00000421386.1 link	c.24G>T	p.Trp8Cys	missense_variant	Exon 2 of 2	3		ENSP00000394702.1	C9JQI2
SCG2	ENST00000433889.1 link	c.24G>T	p.Trp8Cys	missense_variant	Exon 3 of 3	4		ENSP00000415468.1	C9JDT0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000823

AC:

AN:

243102

Hom.:

AF XY:

0.00

AC XY:

AN XY:

131918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000904

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000279

AC:

AN:

1434890

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

708524

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000769

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.15e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 19, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.24G>T (p.W8C) alteration is located in exon 2 (coding exon 1) of the SCG2 gene. This alteration results from a G to T substitution at nucleotide position 24, causing the tryptophan (W) at amino acid position 8 to be replaced by a cysteine (C). 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

0.12

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.66

DEOGEN2

Benign

0.23

T;.;.

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.70

T;T;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.16

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.1

L;.;.

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.6

N;D;D

REVEL

Benign

0.090

Sift

Benign

0.21

T;D;T

Sift4G

Benign

0.20

T;D;.

Polyphen

0.56

P;.;.

Vest4

0.19

MutPred

0.35

Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);

MVP

0.29

MPC

0.21

ClinPred

0.17

GERP RS

1.5

Varity_R

0.15

gMVP

0.30

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over