17-45846317-A-T

Position:

• chr17-45846317-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_175882.3(SPPL2C):​c.1411A>T​(p.Ile471Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I471V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPPL2C NM_175882.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.896

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]

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

ACMG classification

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=0.25748032).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPPL2C	NM_175882.3	c.1411A>T	p.Ile471Phe	missense_variant	1/1	ENST00000329196.7	NP_787078.2
MAPT-AS1	NR_024559.1	n.35-2156T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPPL2C	ENST00000329196.7	c.1411A>T	p.Ile471Phe	missense_variant	1/1		NM_175882.3	ENSP00000332488	P1
MAPT-AS1	ENST00000634876.2	n.183-2156T>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 108

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	14
DANN	Benign	0.64
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.93	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.042
Sift	Benign	0.10	T
Sift4G	Uncertain	0.058	T
Polyphen		0.17	B
Vest4		0.18
MutPred		0.53		Gain of sheet (P = 0.0827);
MVP		0.040
MPC		0.29
ClinPred		0.54	D
GERP RS		0.83
Varity_R		0.15
gMVP		0.46

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.

Other links and lift over

hg19: chr17-43923683;