chr17-45844952-A-C

Variant names:

• chr17-45844952-A-C
• rs758977730
• NM_175882.3:c.46A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_175882.3(SPPL2C):​c.46A>C​(p.Ile16Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I16S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: SPPL2C NM_175882.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.15
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.027173072).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPPL2C	NM_175882.3	MANE Select	c.46A>C	p.Ile16Leu	missense	Exon 1 of 1	NP_787078.2	Q8IUH8
	MAPT-AS1	NR_024559.1		n.35-791T>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPPL2C	ENST00000329196.7	TSL:6 MANE Select	c.46A>C	p.Ile16Leu	missense	Exon 1 of 1	ENSP00000332488.5	Q8IUH8
	MAPT-AS1	ENST00000579599.1	TSL:1	n.903-791T>G		intron	N/A
	MAPT-AS1	ENST00000579244.1	TSL:2	n.122-791T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249692 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461622 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 727084

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111858

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74332

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.0030
DANN	Benign	0.57
DEOGEN2	Benign	0.0039	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0070	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.0	N
PhyloP100		-4.2
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.36	N
REVEL	Benign	0.025
Sift	Benign	0.60	T
Sift4G	Benign	0.86	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.33		Loss of sheet (P = 0.0315)
MVP		0.014
MPC		0.11
ClinPred		0.031	T
GERP RS		-8.8
PromoterAI		0.021	Neutral
Varity_R		0.035
gMVP		0.30
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs758977730; hg19: chr17-43922318;