NM_014752.3:c.40A>C

Variant names:

• chr11-74949325-A-C
• rs1054747868
• NM_014752.3:c.40A>C

Variant summary

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

The NM_014752.3(SPCS2):​c.40A>C​(p.Ser14Arg) 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. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S14G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SPCS2 NM_014752.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.68

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]

XRRA1 (HGNC:18868): (X-ray radiation resistance associated 1) Involved in response to X-ray. Located in cytoplasm and nuclear body. [provided by Alliance of Genome Resources, Apr 2022]

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=0.0491367).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPCS2	NM_014752.3	c.40A>C	p.Ser14Arg	missense_variant	Exon 1 of 5	ENST00000263672.11	NP_055567.2
XRRA1	NM_001378157.1	c.-470T>G		upstream_gene_variant		ENST00000684022.1	NP_001365086.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPCS2	ENST00000263672.11	c.40A>C	p.Ser14Arg	missense_variant	Exon 1 of 5	1	NM_014752.3	ENSP00000263672.6
XRRA1	ENST00000684022.1	c.-470T>G		upstream_gene_variant			NM_001378157.1	ENSP00000507107.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000654 AC: 1 AN: 152864 Hom.: 0 AF XY: 0.0000123 AC XY: 1 AN XY: 81242

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000168

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.15e-7 AC: 1 AN: 1398316 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 689744

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.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	18
DANN	Benign	0.42
DEOGEN2	Benign	0.021	T;T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.67	T;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.049	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;.;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.24	N;.;N;N
REVEL	Benign	0.099
Sift	Benign	0.17	T;.;D;T
Sift4G	Benign	0.32	T;T;T;T
Polyphen		0.0070	B;.;.;.
Vest4		0.29
MutPred		0.28		Loss of glycosylation at S14 (P = 9e-04);Loss of glycosylation at S14 (P = 9e-04);Loss of glycosylation at S14 (P = 9e-04);Loss of glycosylation at S14 (P = 9e-04);
MVP		0.068
MPC		1.1
ClinPred		0.085	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.076
gMVP		0.52

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: rs1054747868; hg19: chr11-74660370;