rs12373139

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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: 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
• Publications: 59 publications found

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=0.006171018).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175882.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPPL2C	NM_175882.3	MANE Select	c.1858G>A	p.Gly620Arg	missense	Exon 1 of 1	NP_787078.2
	MAPT-AS1	NR_024559.1		n.35-2603C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPPL2C	ENST00000329196.7	TSL:6 MANE Select	c.1858G>A	p.Gly620Arg	missense	Exon 1 of 1	ENSP00000332488.5
	MAPT-AS1	ENST00000579599.1	TSL:1	n.903-2603C>T		intron	N/A
	MAPT-AS1	ENST00000579244.1	TSL:2	n.122-2603C>T		intron	N/A

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

GnomAD2 exomes AF: 0.145 AC: 36480 AN: 251236 AF XY: 0.149

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 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

African (AFR) AF: 0.0364 AC: 1219 AN: 33478

American (AMR) AF: 0.125 AC: 5606 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 6708 AN: 26134

East Asian (EAS) AF: 0.000882 AC: 35 AN: 39698

South Asian (SAS) AF: 0.0797 AC: 6872 AN: 86256

European-Finnish (FIN) AF: 0.0722 AC: 3853 AN: 53358

Middle Eastern (MID) AF: 0.201 AC: 1161 AN: 5768

European-Non Finnish (NFE) AF: 0.222 AC: 246589 AN: 1111988

Other (OTH) AF: 0.177 AC: 10698 AN: 60394

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

African (AFR) AF: 0.0428 AC: 1780 AN: 41556

American (AMR) AF: 0.176 AC: 2684 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 836 AN: 3472

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5178

South Asian (SAS) AF: 0.0744 AC: 359 AN: 4824

European-Finnish (FIN) AF: 0.0650 AC: 690 AN: 10620

Middle Eastern (MID) AF: 0.219 AC: 64 AN: 292

European-Non Finnish (NFE) AF: 0.217 AC: 14748 AN: 67980

Other (OTH) AF: 0.183 AC: 385 AN: 2104

Alfa AF: 0.194 Hom.: 8943

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 v4.9

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
PhyloP100		-0.062
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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12373139; hg19: chr17-43924130; COSMIC: COSV61292470;