Variant rs17763658 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_175882.3(SPPL2C):c.368G>A(p.Arg123Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0736 in 1,613,782 control chromosomes in the GnomAD database, including 4,597 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.078 ( 487 hom., cov: 33)

Exomes 𝑓: 0.073 ( 4110 hom. )

Consequence

SPPL2C
NM_175882.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.36

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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037270188).

BP6

Variant 17-45845274-G-A is Benign according to our data. Variant chr17-45845274-G-A is described in ClinVar as [Benign]. Clinvar id is 1288972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPPL2C	NM_175882.3 link	c.368G>A	p.Arg123Gln	missense_variant	Exon 1 of 1	ENST00000329196.7	NP_787078.2	Q8IUH8
MAPT-AS1	NR_024559.1 link	n.35-1113C>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.368G>A	p.Arg123Gln	missense_variant	Exon 1 of 1	6	NM_175882.3	ENSP00000332488.5		Q8IUH8

Frequencies

GnomAD3 genomes

AF:

0.0784

AC:

11934

AN:

152126

Hom.:

484

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0797

Gnomad AMI

AF:

0.0537

Gnomad AMR

AF:

0.0804

Gnomad ASJ

AF:

0.0495

Gnomad EAS

AF:

0.121

Gnomad SAS

AF:

0.0918

Gnomad FIN

AF:

0.110

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0702

Gnomad OTH

AF:

0.0746

GnomAD3 exomes

AF:

0.0798

AC:

20004

AN:

250692

Hom.:

812

AF XY:

0.0792

AC XY:

10742

AN XY:

135604

show subpopulations

Gnomad AFR exome

AF:

0.0814

Gnomad AMR exome

AF:

0.0814

Gnomad ASJ exome

AF:

0.0455

Gnomad EAS exome

AF:

0.111

Gnomad SAS exome

AF:

0.0886

Gnomad FIN exome

AF:

0.104

Gnomad NFE exome

AF:

0.0699

Gnomad OTH exome

AF:

0.0812

GnomAD4 exome

AF:

0.0731

AC:

106897

AN:

1461538

Hom.:

4110

Cov.:

AF XY:

0.0737

AC XY:

53578

AN XY:

727088

show subpopulations

Gnomad4 AFR exome

AF:

0.0798

Gnomad4 AMR exome

AF:

0.0797

Gnomad4 ASJ exome

AF:

0.0509

Gnomad4 EAS exome

AF:

0.121

Gnomad4 SAS exome

AF:

0.0872

Gnomad4 FIN exome

AF:

0.107

Gnomad4 NFE exome

AF:

0.0687

Gnomad4 OTH exome

AF:

0.0759

GnomAD4 genome

AF:

0.0785

AC:

11951

AN:

152244

Hom.:

487

Cov.:

AF XY:

0.0821

AC XY:

6107

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0798

Gnomad4 AMR

AF:

0.0802

Gnomad4 ASJ

AF:

0.0495

Gnomad4 EAS

AF:

0.122

Gnomad4 SAS

AF:

0.0915

Gnomad4 FIN

AF:

0.110

Gnomad4 NFE

AF:

0.0702

Gnomad4 OTH

AF:

0.0766

Alfa

AF:

0.0690

Hom.:

397

Bravo

AF:

0.0767

TwinsUK

AF:

0.0650

AC:

241

ALSPAC

AF:

0.0680

AC:

262

ESP6500AA

AF:

0.0781

AC:

344

ESP6500EA

AF:

0.0685

AC:

589

ExAC

AF:

0.0796

AC:

9667

Asia WGS

AF:

0.111

AC:

384

AN:

3478

EpiCase

AF:

0.0677

EpiControl

AF:

0.0679

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2020	This variant is associated with the following publications: (PMID: 24166410) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.73

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0039

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0037

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.6

REVEL

Benign

0.11

Sift

Benign

0.091

Sift4G

Benign

0.069

Polyphen

0.96

Vest4

0.021

MPC

0.21

ClinPred

0.018

GERP RS

0.47

Varity_R

0.060

gMVP

0.20

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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