2-223598876-G-A

Variant names:

• chr2-223598876-G-A
• NM_003469.5:c.407C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003469.5(SCG2):​c.407C>T​(p.Ala136Val) 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. 15/21 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: 1.05

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 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=0.042022318).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCG2	NM_003469.5	c.407C>T	p.Ala136Val	missense_variant	Exon 2 of 2	ENST00000305409.3	NP_003460.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCG2	ENST00000305409.3	c.407C>T	p.Ala136Val	missense_variant	Exon 2 of 2	1	NM_003469.5	ENSP00000304133.2
SCG2	ENST00000421386.1	c.407C>T	p.Ala136Val	missense_variant	Exon 2 of 2	3		ENSP00000394702.1
SCG2	ENST00000433889.1	c.*30C>T		downstream_gene_variant		4		ENSP00000415468.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.407C>T (p.A136V) 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 407, causing the alanine (A) at amino acid position 136 to be replaced by a valine (V). 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	0.076
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	11
DANN	Benign	0.67
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.042	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.9	M;.
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.054
Sift	Benign	0.25	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.0	B;.
Vest4		0.063
MutPred		0.22		Loss of phosphorylation at S139 (P = 0.1596);Loss of phosphorylation at S139 (P = 0.1596);
MVP		0.12
MPC		0.063
ClinPred		0.051	T
GERP RS		1.6
Varity_R		0.039
gMVP		0.099

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-224463594;