chr17-45845220-C-T

Variant names:

• chr17-45845220-C-T
• rs139470538
• NM_175882.3:c.314C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_175882.3(SPPL2C):​c.314C>T​(p.Thr105Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000531 in 1,613,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00056 (0 hom.)
• Consequence: SPPL2C NM_175882.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.14
• Publications: 6 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06499103).

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.314C>T	p.Thr105Met	missense	Exon 1 of 1	NP_787078.2	Q8IUH8
	MAPT-AS1	NR_024559.1		n.35-1059G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPPL2C	ENST00000329196.7	TSL:6 MANE Select	c.314C>T	p.Thr105Met	missense	Exon 1 of 1	ENSP00000332488.5	Q8IUH8
	MAPT-AS1	ENST00000579599.1	TSL:1	n.903-1059G>A		intron	N/A
	MAPT-AS1	ENST00000579244.1	TSL:2	n.122-1059G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152150 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000291 AC: 73 AN: 250688 AF XY: 0.000273

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000521

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000563 AC: 823 AN: 1461580 Hom.: 0 Cov.: 30 AF XY: 0.000536 AC XY: 390 AN XY: 727078

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000268 AC: 12 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86250

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53258

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

European-Non Finnish (NFE) AF: 0.000691 AC: 768 AN: 1111886

Other (OTH) AF: 0.000530 AC: 32 AN: 60390

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152268 Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19 AN XY: 74442

African (AFR) AF: 0.000168 AC: 7 AN: 41550

American (AMR) AF: 0.000196 AC: 3 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000432 Hom.: 0

Bravo AF: 0.000268

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000280 AC: 34

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000830

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	0.089
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0044	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.1
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.082
Sift	Benign	0.033	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.98	D
Vest4		0.11
MVP		0.014
MPC		0.49
ClinPred		0.064	T
GERP RS		0.36
PromoterAI		-0.0026	Neutral
Varity_R		0.025
gMVP		0.33
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: rs139470538; hg19: chr17-43922586; COSMIC: COSV61292950; COSMIC: COSV61292950;