Genetic Variant NM_014752.3:c.40A>G (chr11-74949325-A-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_014752.3(SPCS2):c.40A>G(p.Ser14Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,550,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SPCS2
NM_014752.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.68

Publications

0 publications found

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:

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]

XRRA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020514935).

BP6

Variant 11-74949325-A-G is Benign according to our data. Variant chr11-74949325-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3168711.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 17 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014752.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPCS2	NM_014752.3	MANE Select	c.40A>G	p.Ser14Gly	missense	Exon 1 of 5	NP_055567.2	Q15005
XRRA1	NM_001378157.1	MANE Select	c.-470T>C		upstream_gene	N/A	NP_001365086.1	A0A804HIK0
XRRA1	NM_182969.4		c.-470T>C		upstream_gene	N/A	NP_892014.1	Q6P2D8-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPCS2	ENST00000263672.11	TSL:1 MANE Select	c.40A>G	p.Ser14Gly	missense	Exon 1 of 5	ENSP00000263672.6	Q15005
SPCS2	ENST00000532972.5	TSL:2	c.40A>G	p.Ser14Gly	missense	Exon 1 of 6	ENSP00000436759.1	E9PI68
SPCS2	ENST00000931774.1		c.40A>G	p.Ser14Gly	missense	Exon 1 of 6	ENSP00000601833.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152192

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000654

AC:

AN:

152864

AF XY:

0.0000123

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000122

AC:

AN:

1398316

Hom.:

Cov.:

AF XY:

0.0000116

AC XY:

AN XY:

689744

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31508

American (AMR)

AF:

0.00

AC:

AN:

35288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25120

East Asian (EAS)

AF:

0.00

AC:

AN:

35722

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79176

European-Finnish (FIN)

AF:

0.0000203

AC:

AN:

49222

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5678

European-Non Finnish (NFE)

AF:

0.0000130

AC:

AN:

1078658

Other (OTH)

AF:

0.0000173

AC:

AN:

57944

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000641

Hom.:

Bravo

AF:

0.0000227

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.049

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.42

DEOGEN2

Benign

0.011

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.061

LIST_S2

Benign

0.50

M_CAP

Benign

0.0053

MetaRNN

Benign

0.021

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

PhyloP100

1.7

PrimateAI

Benign

0.42

PROVEAN

Benign

0.52

REVEL

Benign

0.043

Sift

Benign

0.55

Sift4G

Benign

0.70

Polyphen

0.0

Vest4

0.17

MutPred

0.16

Loss of glycosylation at S14 (P = 9e-04)

MVP

0.082

MPC

0.91

ClinPred

0.047

GERP RS

2.4

PromoterAI

0.089

Neutral

(source)

Varity_R

0.063

gMVP

0.41

Mutation Taster

=98/2

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over