rs17763658

Variant names:

• chr17-45845274-G-A
• rs17763658
• NM_175882.3:c.368G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_175882.3(SPPL2C):​c.368G>A​(p.Arg123Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0736 in 1,613,782 control chromosomes in the GnomAD database, including 4,597 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R123W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.078 (487 hom., cov: 33)
  • Exomes 𝑓: 0.073 (4110 hom.)
• Consequence: SPPL2C NM_175882.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.36
• Publications: 19 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037270188).
• BP6: Variant 17-45845274-G-A is Benign according to our data. Variant chr17-45845274-G-A is described in ClinVar as Benign. ClinVar VariationId is 1288972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.114 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.368G>A	p.Arg123Gln	missense	Exon 1 of 1	NP_787078.2
	MAPT-AS1	NR_024559.1		n.35-1113C>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.368G>A	p.Arg123Gln	missense	Exon 1 of 1	ENSP00000332488.5
	MAPT-AS1	ENST00000579599.1	TSL:1	n.903-1113C>T		intron	N/A
	MAPT-AS1	ENST00000579244.1	TSL:2	n.122-1113C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0784 AC: 11934 AN: 152126 Hom.: 484 Cov.: 33

Gnomad AFR AF: 0.0797

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0804

Gnomad ASJ AF: 0.0495

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.0918

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0702

Gnomad OTH AF: 0.0746

GnomAD2 exomes AF: 0.0798 AC: 20004 AN: 250692 AF XY: 0.0792

Gnomad AFR exome AF: 0.0814

Gnomad AMR exome AF: 0.0814

Gnomad ASJ exome AF: 0.0455

Gnomad EAS exome AF: 0.111

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.0699

Gnomad OTH exome AF: 0.0812

GnomAD4 exome AF: 0.0731 AC: 106897 AN: 1461538 Hom.: 4110 Cov.: 30 AF XY: 0.0737 AC XY: 53578 AN XY: 727088

African (AFR) AF: 0.0798 AC: 2672 AN: 33480

American (AMR) AF: 0.0797 AC: 3563 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0509 AC: 1330 AN: 26132

East Asian (EAS) AF: 0.121 AC: 4789 AN: 39694

South Asian (SAS) AF: 0.0872 AC: 7525 AN: 86250

European-Finnish (FIN) AF: 0.107 AC: 5716 AN: 53198

Middle Eastern (MID) AF: 0.0650 AC: 375 AN: 5766

European-Non Finnish (NFE) AF: 0.0687 AC: 76346 AN: 1111916

Other (OTH) AF: 0.0759 AC: 4581 AN: 60386

GnomAD4 genome AF: 0.0785 AC: 11951 AN: 152244 Hom.: 487 Cov.: 33 AF XY: 0.0821 AC XY: 6107 AN XY: 74430

African (AFR) AF: 0.0798 AC: 3318 AN: 41560

American (AMR) AF: 0.0802 AC: 1227 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0495 AC: 172 AN: 3472

East Asian (EAS) AF: 0.122 AC: 627 AN: 5154

South Asian (SAS) AF: 0.0915 AC: 442 AN: 4830

European-Finnish (FIN) AF: 0.110 AC: 1168 AN: 10612

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0702 AC: 4772 AN: 67994

Other (OTH) AF: 0.0766 AC: 162 AN: 2114

Alfa AF: 0.0710 Hom.: 644

Bravo AF: 0.0767

TwinsUK AF: 0.0650 AC: 241

ALSPAC AF: 0.0680 AC: 262

ESP6500AA AF: 0.0781 AC: 344

ESP6500EA AF: 0.0685 AC: 589

ExAC AF: 0.0796 AC: 9667

Asia WGS AF: 0.111 AC: 384 AN: 3478

EpiCase AF: 0.0677

EpiControl AF: 0.0679

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0039	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.4
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.11
Sift	Benign	0.091	T
Sift4G	Benign	0.069	T
Polyphen		0.96	P
Vest4		0.021
MPC		0.21
ClinPred		0.018	T
GERP RS		0.47
PromoterAI		0.020	Neutral
Varity_R		0.060
gMVP		0.20
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17763658; hg19: chr17-43922640; COSMIC: COSV61291901; COSMIC: COSV61291901;