rs377400543

Variant names:

• chr17-45845151-G-A
• rs377400543
• NM_175882.3:c.245G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-45845151-G-A
• chr17-45845151-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_175882.3(SPPL2C):​c.245G>A​(p.Arg82His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000583 in 1,611,622 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. R82C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: SPPL2C NM_175882.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.06
• Publications: 2 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08061609).

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.245G>A	p.Arg82His	missense	Exon 1 of 1	NP_787078.2	Q8IUH8
	MAPT-AS1	NR_024559.1		n.35-990C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPPL2C	ENST00000329196.7	TSL:6 MANE Select	c.245G>A	p.Arg82His	missense	Exon 1 of 1	ENSP00000332488.5	Q8IUH8
	MAPT-AS1	ENST00000579599.1	TSL:1	n.903-990C>T		intron	N/A
	MAPT-AS1	ENST00000579244.1	TSL:2	n.122-990C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152060 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 249208 AF XY: 0.00000741

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000617 AC: 90 AN: 1459562 Hom.: 0 Cov.: 30 AF XY: 0.0000510 AC XY: 37 AN XY: 725632

African (AFR) AF: 0.0000299 AC: 1 AN: 33430

American (AMR) AF: 0.00 AC: 0 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39612

South Asian (SAS) AF: 0.00 AC: 0 AN: 86216

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000693 AC: 77 AN: 1110328

Other (OTH) AF: 0.000149 AC: 9 AN: 60284

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152060 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74278

African (AFR) AF: 0.0000242 AC: 1 AN: 41396

American (AMR) AF: 0.000131 AC: 2 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.000136 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

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	0.063
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.0023	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.1
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.021
Sift	Benign	0.13	T
Sift4G	Benign	0.20	T
Polyphen		0.20	B
Vest4		0.082
MVP		0.030
MPC		0.27
ClinPred		0.062	T
GERP RS		3.6
PromoterAI		-0.012	Neutral
Varity_R		0.061
gMVP		0.23
Mutation Taster		=94/6	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: rs377400543; hg19: chr17-43922517; COSMIC: COSV61292097; COSMIC: COSV61292097;