chr17-45846317-A-G

Variant names:

• chr17-45846317-A-G
• rs12185268
• NM_175882.3:c.1411A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_175882.3(SPPL2C):​c.1411A>G​(p.Ile471Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,613,976 control chromosomes in the GnomAD database, including 32,784 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.14 (2142 hom., cov: 33)
  • Exomes 𝑓: 0.19 (30642 hom.)
• 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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018708348).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPPL2C	NM_175882.3	c.1411A>G	p.Ile471Val	missense_variant	Exon 1 of 1	ENST00000329196.7	NP_787078.2
MAPT-AS1	NR_024559.1	n.35-2156T>C		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPPL2C	ENST00000329196.7	c.1411A>G	p.Ile471Val	missense_variant	Exon 1 of 1	6	NM_175882.3	ENSP00000332488.5

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21854 AN: 152070 Hom.: 2144 Cov.: 33

Gnomad AFR AF: 0.0431

Gnomad AMI AF: 0.278

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0742

Gnomad FIN AF: 0.0652

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.186

GnomAD2 exomes AF: 0.145 AC: 36513 AN: 251412 AF XY: 0.149

Gnomad AFR exome AF: 0.0399

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.255

Gnomad EAS exome AF: 0.000652

Gnomad FIN exome AF: 0.0677

Gnomad NFE exome AF: 0.214

Gnomad OTH exome AF: 0.175

GnomAD4 exome AF: 0.193 AC: 282745 AN: 1461788 Hom.: 30642 Cov.: 108 AF XY: 0.191 AC XY: 138904 AN XY: 727196

Gnomad4 AFR exome AF: 0.0365 AC: 1223 AN: 33480

Gnomad4 AMR exome AF: 0.125 AC: 5612 AN: 44724

Gnomad4 ASJ exome AF: 0.257 AC: 6708 AN: 26136

Gnomad4 EAS exome AF: 0.000882 AC: 35 AN: 39700

Gnomad4 SAS exome AF: 0.0797 AC: 6871 AN: 86256

Gnomad4 FIN exome AF: 0.0721 AC: 3844 AN: 53336

Gnomad4 NFE exome AF: 0.222 AC: 246593 AN: 1111996

Gnomad4 Remaining exome AF: 0.177 AC: 10698 AN: 60392

GnomAD4 genome AF: 0.144 AC: 21844 AN: 152188 Hom.: 2142 Cov.: 33 AF XY: 0.134 AC XY: 9998 AN XY: 74410

Gnomad4 AFR AF: 0.0430 AC: 0.0430175 AN: 0.0430175

Gnomad4 AMR AF: 0.176 AC: 0.175736 AN: 0.175736

Gnomad4 ASJ AF: 0.241 AC: 0.240922 AN: 0.240922

Gnomad4 EAS AF: 0.00154 AC: 0.001545 AN: 0.001545

Gnomad4 SAS AF: 0.0742 AC: 0.0742123 AN: 0.0742123

Gnomad4 FIN AF: 0.0652 AC: 0.0652461 AN: 0.0652461

Gnomad4 NFE AF: 0.217 AC: 0.217295 AN: 0.217295

Gnomad4 OTH AF: 0.183 AC: 0.183239 AN: 0.183239

Alfa AF: 0.194 Hom.: 14223

Bravo AF: 0.148

TwinsUK AF: 0.232 AC: 862

ALSPAC AF: 0.239 AC: 923

ESP6500AA AF: 0.0461 AC: 203

ESP6500EA AF: 0.224 AC: 1928

ExAC AF: 0.144 AC: 17517

Asia WGS AF: 0.0310 AC: 110 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.39
DANN	Benign	0.44
DEOGEN2	Benign	0.0022	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0029	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.3	N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.022
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0040	B
Vest4		0.0060
MPC		0.094
ClinPred		0.0010	T
GERP RS		0.83
Varity_R		0.026
gMVP		0.16
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12185268; hg19: chr17-43923683;