Variant 17-45845043-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_175882.3(SPPL2C):c.137A>G(p.Tyr46Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,614,036 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0023 ( 11 hom. )

Consequence

SPPL2C
NM_175882.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.00

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.064667016).

BP6

Variant 17-45845043-A-G is Benign according to our data. Variant chr17-45845043-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 787567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPPL2C	NM_175882.3 linkuse as main transcript	c.137A>G	p.Tyr46Cys	missense_variant	1/1	ENST00000329196.7
MAPT-AS1	NR_024559.1 linkuse as main transcript	n.35-882T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPPL2C	ENST00000329196.7 linkuse as main transcript	c.137A>G	p.Tyr46Cys	missense_variant	1/1		NM_175882.3	P1
MAPT-AS1	ENST00000634876.2 linkuse as main transcript	n.183-882T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00187

AC:

284

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00187

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00300

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00197

AC:

496

AN:

251316

Hom.:

AF XY:

0.00211

AC XY:

286

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00252

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00292

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00227

AC:

3325

AN:

1461836

Hom.:

Cov.:

AF XY:

0.00234

AC XY:

1705

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.00136

Gnomad4 ASJ exome

AF:

0.000804

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00270

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.00255

Gnomad4 OTH exome

AF:

0.00227

GnomAD4 genome

AF:

0.00187

AC:

285

AN:

152200

Hom.:

Cov.:

AF XY:

0.00181

AC XY:

135

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.000506

Gnomad4 AMR

AF:

0.00261

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00300

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00264

Hom.:

Bravo

AF:

0.00177

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00194

AC:

236

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00333

EpiControl

AF:

0.00255

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 04, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	SPPL2C: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.064

Eigen

Uncertain

0.29

Eigen_PC

Benign

0.17

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.64

M_CAP

Benign

0.0080

MetaRNN

Benign

0.065

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

MutationTaster

Benign

0.64

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-5.3

REVEL

Benign

0.16

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.99

Vest4

0.68

MVP

0.29

MPC

0.58

ClinPred

0.069

GERP RS

4.6

Varity_R

0.20

gMVP

0.72

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

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