chr2-223597892-G-A

Position:

• chr2-223597892-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003469.5(SCG2):​c.1391C>T​(p.Pro464Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: SCG2 NM_003469.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.58

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]

ACMG classification

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=0.22170925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCG2	NM_003469.5	c.1391C>T	p.Pro464Leu	missense_variant	2/2	ENST00000305409.3	NP_003460.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCG2	ENST00000305409.3	c.1391C>T	p.Pro464Leu	missense_variant	2/2	1	NM_003469.5	ENSP00000304133	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2021

The c.1391C>T (p.P464L) alteration is located in exon 2 (coding exon 1) of the SCG2 gene. This alteration results from a C to T substitution at nucleotide position 1391, causing the proline (P) at amino acid position 464 to be replaced by a leucine (L). 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	0.088
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	14
DANN	Benign	0.40
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.18	N
MutationTaster	Benign	0.80	D
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.032
Sift	Benign	0.26	T
Sift4G	Uncertain	0.055	T
Polyphen		0.0090	B
Vest4		0.095
MVP		0.068
MPC		0.064
ClinPred		0.095	T
GERP RS		3.0
Varity_R		0.047
gMVP		0.34

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

Other links and lift over

dbSNP: rs375918223; hg19: chr2-224462610;