NM_175882.3:c.1858G>A

Variant names:

• chr17-45846764-G-A
• rs12373139
• NM_175882.3:c.1858G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_175882.3(SPPL2C):​c.1858G>A​(p.Gly620Arg) 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 1,614,024 control chromosomes in the GnomAD database, including 32,778 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 (2134 hom., cov: 33)
  • Exomes 𝑓: 0.19 (30644 hom.)
• Consequence: SPPL2C NM_175882.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0620

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006171018).
• 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.1858G>A	p.Gly620Arg	missense_variant	Exon 1 of 1	ENST00000329196.7	NP_787078.2
MAPT-AS1	NR_024559.1	n.35-2603C>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPPL2C	ENST00000329196.7	c.1858G>A	p.Gly620Arg	missense_variant	Exon 1 of 1	6	NM_175882.3	ENSP00000332488.5

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21817 AN: 152110 Hom.: 2136 Cov.: 33

Gnomad AFR AF: 0.0429

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0744

Gnomad FIN AF: 0.0650

Gnomad MID AF: 0.223

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.186

GnomAD3 exomes AF: 0.145 AC: 36480 AN: 251236 Hom.: 3544 AF XY: 0.149 AC XY: 20196 AN XY: 135804

Gnomad AFR exome AF: 0.0397

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.000653

Gnomad SAS exome AF: 0.0762

Gnomad FIN exome AF: 0.0680

Gnomad NFE exome AF: 0.214

Gnomad OTH exome AF: 0.175

GnomAD4 exome AF: 0.193 AC: 282741 AN: 1461796 Hom.: 30644 Cov.: 49 AF XY: 0.191 AC XY: 138898 AN XY: 727188

Gnomad4 AFR exome AF: 0.0364

Gnomad4 AMR exome AF: 0.125

Gnomad4 ASJ exome AF: 0.257

Gnomad4 EAS exome AF: 0.000882

Gnomad4 SAS exome AF: 0.0797

Gnomad4 FIN exome AF: 0.0722

Gnomad4 NFE exome AF: 0.222

Gnomad4 OTH exome AF: 0.177

GnomAD4 genome AF: 0.143 AC: 21807 AN: 152228 Hom.: 2134 Cov.: 33 AF XY: 0.134 AC XY: 9987 AN XY: 74440

Gnomad4 AFR AF: 0.0428

Gnomad4 AMR AF: 0.176

Gnomad4 ASJ AF: 0.241

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.0744

Gnomad4 FIN AF: 0.0650

Gnomad4 NFE AF: 0.217

Gnomad4 OTH AF: 0.183

Alfa AF: 0.202 Hom.: 6575

Bravo AF: 0.148

TwinsUK AF: 0.233 AC: 865

ALSPAC AF: 0.241 AC: 928

ESP6500AA AF: 0.0456 AC: 201

ESP6500EA AF: 0.224 AC: 1928

ExAC AF: 0.144 AC: 17514

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	0.078
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.8
DANN	Benign	0.48
DEOGEN2	Benign	0.0048	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.34	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.063
Sift	Benign	0.36	T
Sift4G	Uncertain	0.051	T
Polyphen		0.0020	B
Vest4		0.12
MutPred		0.036		Gain of helix (P = 0.0325);
MPC		0.14
ClinPred		0.0039	T
GERP RS		-2.5
Varity_R		0.041
gMVP		0.074

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs12373139; hg19: chr17-43924130; COSMIC: COSV61292470; COSMIC: COSV61292470;