dbSNP rs242944: SPPL2C:p.Arg303His (chr17-45845814-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.908G>A(p.Arg303His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.583 in 1,607,550 control chromosomes in the GnomAD database, including 279,263 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.54 ( 23397 hom., cov: 34)

Exomes 𝑓: 0.59 ( 255866 hom. )

Consequence

SPPL2C
NM_175882.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.00900

Publications

47 publications found

Variant links:

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=2.1664175E-6).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPPL2C	NM_175882.3 link	c.908G>A	p.Arg303His	missense_variant	Exon 1 of 1	ENST00000329196.7	NP_787078.2	Q8IUH8
MAPT-AS1	NR_024559.1 link	n.35-1653C>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.908G>A	p.Arg303His	missense_variant	Exon 1 of 1	6	NM_175882.3	ENSP00000332488.5		Q8IUH8

Frequencies

GnomAD3 genomes

AF:

0.542

AC:

82423

AN:

152002

Hom.:

23390

Cov.:

show subpopulations

Gnomad AFR

AF:

0.385

Gnomad AMI

AF:

0.594

Gnomad AMR

AF:

0.607

Gnomad ASJ

AF:

0.541

Gnomad EAS

AF:

0.802

Gnomad SAS

AF:

0.768

Gnomad FIN

AF:

0.710

Gnomad MID

AF:

0.551

Gnomad NFE

AF:

0.561

Gnomad OTH

AF:

0.528

GnomAD2 exomes

AF:

0.626

AC:

154584

AN:

246836

AF XY:

0.630

show subpopulations

Gnomad AFR exome

AF:

0.372

Gnomad AMR exome

AF:

0.711

Gnomad ASJ exome

AF:

0.534

Gnomad EAS exome

AF:

0.800

Gnomad FIN exome

AF:

0.719

Gnomad NFE exome

AF:

0.567

Gnomad OTH exome

AF:

0.602

GnomAD4 exome

AF:

0.587

AC:

855001

AN:

1455428

Hom.:

255866

Cov.:

AF XY:

0.592

AC XY:

429193

AN XY:

724396

show subpopulations

African (AFR)

AF:

0.371

AC:

12434

AN:

33476

American (AMR)

AF:

0.701

AC:

31346

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.527

AC:

13765

AN:

26136

East Asian (EAS)

AF:

0.806

AC:

32002

AN:

39700

South Asian (SAS)

AF:

0.763

AC:

65813

AN:

86258

European-Finnish (FIN)

AF:

0.704

AC:

33139

AN:

47080

Middle Eastern (MID)

AF:

0.581

AC:

3354

AN:

5768

European-Non Finnish (NFE)

AF:

0.564

AC:

627517

AN:

1111932

Other (OTH)

AF:

0.590

AC:

35631

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

25156

50313

75469

100626

125782

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17612

35224

52836

70448

88060

<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:

0.542

AC:

82448

AN:

152122

Hom.:

23397

Cov.:

AF XY:

0.555

AC XY:

41278

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.384

AC:

15925

AN:

41482

American (AMR)

AF:

0.608

AC:

9297

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.541

AC:

1873

AN:

3464

East Asian (EAS)

AF:

0.801

AC:

4140

AN:

5168

South Asian (SAS)

AF:

0.769

AC:

3707

AN:

4822

European-Finnish (FIN)

AF:

0.710

AC:

7525

AN:

10606

Middle Eastern (MID)

AF:

0.531

AC:

156

AN:

294

European-Non Finnish (NFE)

AF:

0.561

AC:

38163

AN:

67970

Other (OTH)

AF:

0.530

AC:

1120

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1892

3784

5675

7567

9459

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

716

1432

2148

2864

3580

<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:

0.558

Hom.:

105588

Bravo

AF:

0.526

TwinsUK

AF:

0.558

AC:

2069

ALSPAC

AF:

0.549

AC:

2117

ESP6500AA

AF:

0.391

AC:

1723

ESP6500EA

AF:

0.558

AC:

4803

ExAC

AF:

0.621

AC:

75335

Asia WGS

AF:

0.746

AC:

2593

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.044

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.0033

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0067

LIST_S2

Benign

0.36

MetaRNN

Benign

0.0000022

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.64

PhyloP100

0.0090

PrimateAI

Benign

0.20

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.0090

Sift

Benign

0.31

Sift4G

Benign

0.26

Polyphen

0.026

Vest4

0.0090

MPC

0.14

ClinPred

0.018

GERP RS

-8.5

Varity_R

0.027

gMVP

0.11

Mutation Taster

=98/2

polymorphism (auto)

(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

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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