Genetic Variant NM_175882.3:c.224C>A (chr17-45845130-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_175882.3(SPPL2C):c.224C>A(p.Ser75Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SPPL2C
NM_175882.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.119

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1789378).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPPL2C	NM_175882.3 link	c.224C>A	p.Ser75Tyr	missense_variant	Exon 1 of 1	ENST00000329196.7	NP_787078.2	Q8IUH8
MAPT-AS1	NR_024559.1 link	n.35-969G>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.224C>A	p.Ser75Tyr	missense_variant	Exon 1 of 1	6	NM_175882.3	ENSP00000332488.5		Q8IUH8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458670

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724954

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.016

Eigen

Benign

-0.0070

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.47

M_CAP

Benign

0.0079

MetaRNN

Benign

0.18

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.63

REVEL

Benign

0.11

Sift

Uncertain

0.022

Sift4G

Benign

0.10

Polyphen

0.92

Vest4

0.28

MutPred

0.27

Loss of disorder (P = 0.0345);

MVP

0.048

MPC

0.49

ClinPred

0.49

GERP RS

4.5

Varity_R

0.081

gMVP

0.39

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over