dbSNP rs12373139: SPPL2C:p.Gly620Arg (chr17-45846764-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_175882.3(SPPL2C):c.1858G>A(p.Gly620Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,614,024 control chromosomes in the GnomAD database, including 32,778 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.14 ( 2134 hom., cov: 33)

Exomes 𝑓: 0.19 ( 30644 hom. )

Consequence

SPPL2C
NM_175882.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0620

Publications

59 publications found

Variant links:

COSMIC-nc: COSV61292470

Genes affected

SPPL2C (HGNC:28902): (signal peptide peptidase like 2C) Enables protein homodimerization activity. Predicted to be involved in membrane protein proteolysis. Located in endoplasmic reticulum membrane. Is integral component of cytoplasmic side of endoplasmic reticulum membrane and integral component of lumenal side of endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

SPPL2C links:

MAPT-AS1 (HGNC:43738): (MAPT antisense RNA 1) Implicated in Parkinson's disease. [provided by Alliance of Genome Resources, Apr 2022]

MAPT-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006171018).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPPL2C	NM_175882.3 link	c.1858G>A	p.Gly620Arg	missense_variant	Exon 1 of 1	ENST00000329196.7	NP_787078.2	Q8IUH8
MAPT-AS1	NR_024559.1 link	n.35-2603C>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPPL2C	ENST00000329196.7 link	c.1858G>A	p.Gly620Arg	missense_variant	Exon 1 of 1	6	NM_175882.3	ENSP00000332488.5		Q8IUH8

Frequencies

GnomAD3 genomes

AF:

0.143

AC:

21817

AN:

152110

Hom.:

2136

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0429

Gnomad AMI

AF:

0.277

Gnomad AMR

AF:

0.176

Gnomad ASJ

AF:

0.241

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.0744

Gnomad FIN

AF:

0.0650

Gnomad MID

AF:

0.223

Gnomad NFE

AF:

0.217

Gnomad OTH

AF:

0.186

GnomAD2 exomes

AF:

0.145

AC:

36480

AN:

251236

AF XY:

0.149

show subpopulations

Gnomad AFR exome

AF:

0.0397

Gnomad AMR exome

AF:

0.119

Gnomad ASJ exome

AF:

0.254

Gnomad EAS exome

AF:

0.000653

Gnomad FIN exome

AF:

0.0680

Gnomad NFE exome

AF:

0.214

Gnomad OTH exome

AF:

0.175

GnomAD4 exome

AF:

0.193

AC:

282741

AN:

1461796

Hom.:

30644

Cov.:

AF XY:

0.191

AC XY:

138898

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.0364

AC:

1219

AN:

33478

American (AMR)

AF:

0.125

AC:

5606

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.257

AC:

6708

AN:

26134

East Asian (EAS)

AF:

0.000882

AC:

AN:

39698

South Asian (SAS)

AF:

0.0797

AC:

6872

AN:

86256

European-Finnish (FIN)

AF:

0.0722

AC:

3853

AN:

53358

Middle Eastern (MID)

AF:

0.201

AC:

1161

AN:

5768

European-Non Finnish (NFE)

AF:

0.222

AC:

246589

AN:

1111988

Other (OTH)

AF:

0.177

AC:

10698

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

15872

31744

47615

63487

79359

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.143

AC:

21807

AN:

152228

Hom.:

2134

Cov.:

AF XY:

0.134

AC XY:

9987

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0428

AC:

1780

AN:

41556

American (AMR)

AF:

0.176

AC:

2684

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.241

AC:

836

AN:

3472

East Asian (EAS)

AF:

0.00154

AC:

AN:

5178

South Asian (SAS)

AF:

0.0744

AC:

359

AN:

4824

European-Finnish (FIN)

AF:

0.0650

AC:

690

AN:

10620

Middle Eastern (MID)

AF:

0.219

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.217

AC:

14748

AN:

67980

Other (OTH)

AF:

0.183

AC:

385

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

935

1869

2804

3738

4673

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.194

Hom.:

8943

Bravo

AF:

0.148

TwinsUK

AF:

0.233

AC:

865

ALSPAC

AF:

0.241

AC:

928

ESP6500AA

AF:

0.0456

AC:

201

ESP6500EA

AF:

0.224

AC:

1928

ExAC

AF:

0.144

AC:

17514

Asia WGS

AF:

0.0310

AC:

110

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.85

BayesDel_noAF

Benign

-0.85

CADD

Benign

5.8

(source)

DANN

Benign

0.48

DEOGEN2

Benign

0.0048

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.38

MetaRNN

Benign

0.0062

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.34

PhyloP100

-0.062

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.5

REVEL

Benign

0.063

Sift

Benign

0.36

Sift4G

Uncertain

0.051

Polyphen

0.0020

Vest4

0.12

MutPred

0.036

Gain of helix (P = 0.0325);

MPC

0.14

ClinPred

0.0039

GERP RS

-2.5

Varity_R

0.041

gMVP

0.074

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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.

rs12373139

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over