chr11-74976925-A-G

Position:

• chr11-74976925-A-G

Variant summary

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

The NM_014752.3(SPCS2):​c.563A>G​(p.Glu188Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: SPCS2 NM_014752.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.31

Genes affected

SPCS2 (HGNC:28962): (signal peptidase complex subunit 2) Predicted to enable peptidase activity. Predicted to be involved in protein targeting to ER and signal peptide processing. Predicted to be located in endoplasmic reticulum membrane. Predicted to be part of signal peptidase complex. [provided by Alliance of Genome Resources, Apr 2022]

SPCS2 (HGNC:):

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=0.25986183).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPCS2	NM_014752.3	c.563A>G	p.Glu188Gly	missense_variant	5/5	ENST00000263672.11	NP_055567.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPCS2	ENST00000263672.11	c.563A>G	p.Glu188Gly	missense_variant	5/5	1	NM_014752.3	ENSP00000263672.6

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000756

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

Jan 11, 2023

The c.563A>G (p.E188G) alteration is located in exon 5 (coding exon 5) of the SPCS2 gene. This alteration results from a A to G substitution at nucleotide position 563, causing the glutamic acid (E) at amino acid position 188 to be replaced by a glycine (G). 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	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.061	T;T;T;T;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.26	T;T;T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.2	M;.;.;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.8	D;.;D;D;D
REVEL	Uncertain	0.57
Sift	Benign	0.065	T;.;D;T;D
Sift4G	Benign	0.20	T;T;T;D;T
Polyphen		0.48	P;.;.;.;.
Vest4		0.40
MutPred		0.49		Loss of stability (P = 0.0184);.;.;.;.;
MVP		0.16
MPC		1.5
ClinPred		0.96	D
GERP RS		5.4
Varity_R		0.23
gMVP		0.71

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: rs1948617374; hg19: chr11-74687970;