11-74965067-A-G

Position:

• chr11-74965067-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014752.3(SPCS2):​c.148A>G​(p.Lys50Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SPCS2 NM_014752.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.34

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPCS2	NM_014752.3	c.148A>G	p.Lys50Glu	missense_variant	2/5	ENST00000263672.11	NP_055567.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPCS2	ENST00000263672.11	c.148A>G	p.Lys50Glu	missense_variant	2/5	1	NM_014752.3	ENSP00000263672.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399046 Hom.: 0 Cov.: 29 AF XY: 0.00000145 AC XY: 1 AN XY: 689990

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Apr 19, 2024

The c.148A>G (p.K50E) alteration is located in exon 2 (coding exon 2) of the SPCS2 gene. This alteration results from a A to G substitution at nucleotide position 148, causing the lysine (K) at amino acid position 50 to be replaced by a glutamic acid (E). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;T;T;T;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T;T;T;T;T
M_CAP	Benign	0.0036	T
MetaRNN	Pathogenic	0.90	D;D;D;D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.9	L;.;.;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.4	D;.;D;D;D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0010	D;.;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.77
MutPred		0.80		Loss of ubiquitination at K50 (P = 0.0244);Loss of ubiquitination at K50 (P = 0.0244);Loss of ubiquitination at K50 (P = 0.0244);.;.;
MVP		0.52
MPC		2.5
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.77
gMVP		0.99

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: chr11-74676112;