17-45845135-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_175882.3(SPPL2C):c.229C>T(p.His77Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000853 in 1,610,674 control chromosomes in the GnomAD database, including 15 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 (★).

Frequency

Genomes: 𝑓 0.0046 ( 6 hom., cov: 33)

Exomes 𝑓: 0.00046 ( 9 hom. )

Consequence

SPPL2C
NM_175882.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.807

Publications

1 publications found

Variant links:

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]

SPPL2C links:

MAPT-AS1 (HGNC:43738): (MAPT antisense RNA 1) Implicated in Parkinson's disease. [provided by Alliance of Genome Resources, Apr 2022]

MAPT-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0048868656).

BP6

Variant 17-45845135-C-T is Benign according to our data. Variant chr17-45845135-C-T is described in ClinVar as Benign. ClinVar VariationId is 781369.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00464 (707/152322) while in subpopulation AFR AF = 0.0162 (672/41578). AF 95% confidence interval is 0.0152. There are 6 homozygotes in GnomAd4. There are 333 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

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.229C>T	p.His77Tyr	missense	Exon 1 of 1	NP_787078.2	Q8IUH8
	MAPT-AS1	NR_024559.1		n.35-974G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPPL2C	ENST00000329196.7	TSL:6 MANE Select	c.229C>T	p.His77Tyr	missense	Exon 1 of 1	ENSP00000332488.5	Q8IUH8
MAPT-AS1	ENST00000579599.1	TSL:1	n.903-974G>A		intron	N/A
MAPT-AS1	ENST00000579244.1	TSL:2	n.122-974G>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00465

AC:

707

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

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:

0.0000294

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00120

AC:

299

AN:

249736

AF XY:

0.000703

show subpopulations

Gnomad AFR exome

AF:

0.0165

Gnomad AMR exome

AF:

0.000783

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:

0.000821

GnomAD4 exome

AF:

0.000457

AC:

667

AN:

1458352

Hom.:

Cov.:

AF XY:

0.000378

AC XY:

274

AN XY:

724664

show subpopulations

African (AFR)

AF:

0.0169

AC:

566

AN:

33420

American (AMR)

AF:

0.000940

AC:

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26090

East Asian (EAS)

AF:

0.00

AC:

AN:

39558

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86184

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53206

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1109290

Other (OTH)

AF:

0.000847

AC:

AN:

60188

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

104

157

209

261

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00464

AC:

707

AN:

152322

Hom.:

Cov.:

AF XY:

0.00447

AC XY:

333

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0162

AC:

672

AN:

41578

American (AMR)

AF:

0.00176

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68016

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

108

144

180

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000900

Hom.:

Bravo

AF:

0.00501

ESP6500AA

AF:

0.0157

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00154

AC:

187

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0054

Eigen

Benign

0.074

Eigen_PC

Benign

-0.039

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.45

MetaRNN

Benign

0.0049

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

PhyloP100

0.81

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.9

REVEL

Benign

0.080

Sift

Benign

0.042

Sift4G

Uncertain

0.041

Polyphen

0.85

Vest4

0.27

MVP

0.014

MPC

0.49

ClinPred

0.045

GERP RS

4.2

PromoterAI

-0.0018

Neutral

(source)

Varity_R

0.058

gMVP

0.25

Mutation Taster

=97/3

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over