rs17763658

Positions:

• chr17-45845274-G-A

Variant summary

Our verdict is Benign. Variant got -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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPPL2C	NM_175882.3	c.368G>A	p.Arg123Gln	missense_variant	1/1	ENST00000329196.7	NP_787078.2
MAPT-AS1	NR_024559.1	n.35-1113C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPPL2C	ENST00000329196.7	c.368G>A	p.Arg123Gln	missense_variant	1/1		NM_175882.3	ENSP00000332488	P1
MAPT-AS1	ENST00000634876.2	n.183-1113C>T		intron_variant, non_coding_transcript_variant		5

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

GnomAD3 exomes AF: 0.0798 AC: 20004 AN: 250692 Hom.: 812 AF XY: 0.0792 AC XY: 10742 AN XY: 135604

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 SAS exome AF: 0.0886

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

Gnomad4 AFR exome AF: 0.0798

Gnomad4 AMR exome AF: 0.0797

Gnomad4 ASJ exome AF: 0.0509

Gnomad4 EAS exome AF: 0.121

Gnomad4 SAS exome AF: 0.0872

Gnomad4 FIN exome AF: 0.107

Gnomad4 NFE exome AF: 0.0687

Gnomad4 OTH exome AF: 0.0759

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

Gnomad4 AFR AF: 0.0798

Gnomad4 AMR AF: 0.0802

Gnomad4 ASJ AF: 0.0495

Gnomad4 EAS AF: 0.122

Gnomad4 SAS AF: 0.0915

Gnomad4 FIN AF: 0.110

Gnomad4 NFE AF: 0.0702

Gnomad4 OTH AF: 0.0766

Alfa AF: 0.0690 Hom.: 397

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2020	This variant is associated with the following publications: (PMID: 24166410) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	0.023	P
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
Varity_R		0.060
gMVP		0.20

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

Publications

LitVar

Other links and lift over

dbSNP: rs17763658; hg19: chr17-43922640; COSMIC: COSV61291901; COSMIC: COSV61291901;