Variant 11-74976982-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_014752.3(SPCS2):c.620C>T(p.Ala207Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,445,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SPCS2
NM_014752.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.12

Variant links:

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 links:

SPCS2 (HGNC:):

SPCS2 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=0.10957059).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPCS2	NM_014752.3 linkuse as main transcript	c.620C>T	p.Ala207Val	missense_variant	5/5	ENST00000263672.11	NP_055567.2	Q15005

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPCS2	ENST00000263672.11 linkuse as main transcript	c.620C>T	p.Ala207Val	missense_variant	5/5	1	NM_014752.3	ENSP00000263672.6		Q15005

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000196

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000823

AC:

AN:

242866

Hom.:

AF XY:

0.00000758

AC XY:

AN XY:

131872

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000113

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000277

AC:

AN:

1445264

Hom.:

Cov.:

AF XY:

0.00000418

AC XY:

AN XY:

718036

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000507

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000182

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000132

AC:

AN:

151126

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73736

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000196

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 17, 2024

The c.620C>T (p.A207V) alteration is located in exon 5 (coding exon 5) of the SPCS2 gene. This alteration results from a C to T substitution at nucleotide position 620, causing the alanine (A) at amino acid position 207 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

0.099

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.75

DEOGEN2

Benign

0.020

T;T;T;T;T

Eigen

Benign

-0.098

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.87

D;D;D;D;D

M_CAP

Benign

0.0019

MetaRNN

Benign

0.11

T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.34

N;.;.;.;.

PrimateAI

Uncertain

0.63

PROVEAN

Benign

0.15

N;.;N;N;N

REVEL

Benign

0.079

Sift

Benign

0.22

T;.;T;T;T

Sift4G

Benign

0.66

T;T;T;T;T

Polyphen

0.030

B;.;.;.;.

Vest4

0.19

MutPred

0.56

Loss of disorder (P = 0.1412);.;.;.;.;

MVP

0.043

MPC

1.0

ClinPred

0.26

GERP RS

5.4

Varity_R

0.047

gMVP

0.45

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