Genetic Variant SPPL2C:p.His649His (chr17-45846853-T-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_175882.3(SPPL2C):c.1947T>C(p.His649His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,613,288 control chromosomes in the GnomAD database, including 32,769 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.14 ( 2126 hom., cov: 33)

Exomes 𝑓: 0.19 ( 30643 hom. )

Consequence

SPPL2C
NM_175882.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.13

Publications

55 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.0).

BP7

Synonymous conserved (PhyloP=-3.13 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPPL2C	NM_175882.3 link	c.1947T>C	p.His649His	synonymous_variant	Exon 1 of 1	ENST00000329196.7	NP_787078.2	Q8IUH8
MAPT-AS1	NR_024559.1 link	n.35-2692A>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPPL2C	ENST00000329196.7 link	c.1947T>C	p.His649His	synonymous_variant	Exon 1 of 1	6	NM_175882.3	ENSP00000332488.5		Q8IUH8

Frequencies

GnomAD3 genomes

AF:

0.143

AC:

21808

AN:

152056

Hom.:

2128

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0429

Gnomad AMI

AF:

0.275

Gnomad AMR

AF:

0.176

Gnomad ASJ

AF:

0.241

Gnomad EAS

AF:

0.00155

Gnomad SAS

AF:

0.0739

Gnomad FIN

AF:

0.0648

Gnomad MID

AF:

0.222

Gnomad NFE

AF:

0.217

Gnomad OTH

AF:

0.186

GnomAD2 exomes

AF:

0.145

AC:

36333

AN:

250560

AF XY:

0.149

show subpopulations

Gnomad AFR exome

AF:

0.0400

Gnomad AMR exome

AF:

0.119

Gnomad ASJ exome

AF:

0.254

Gnomad EAS exome

AF:

0.000653

Gnomad FIN exome

AF:

0.0674

Gnomad NFE exome

AF:

0.213

Gnomad OTH exome

AF:

0.175

GnomAD4 exome

AF:

0.193

AC:

282685

AN:

1461114

Hom.:

30643

Cov.:

AF XY:

0.191

AC XY:

138858

AN XY:

726792

show subpopulations

African (AFR)

AF:

0.0365

AC:

1223

AN:

33470

American (AMR)

AF:

0.125

AC:

5611

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.257

AC:

6707

AN:

26130

East Asian (EAS)

AF:

0.000907

AC:

AN:

39690

South Asian (SAS)

AF:

0.0797

AC:

6871

AN:

86254

European-Finnish (FIN)

AF:

0.0720

AC:

3817

AN:

52982

Middle Eastern (MID)

AF:

0.201

AC:

1160

AN:

5768

European-Non Finnish (NFE)

AF:

0.222

AC:

246565

AN:

1111728

Other (OTH)

AF:

0.177

AC:

10695

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

13867

27734

41602

55469

69336

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8224

16448

24672

32896

41120

<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:

0.143

AC:

21798

AN:

152174

Hom.:

2126

Cov.:

AF XY:

0.134

AC XY:

9977

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.0428

AC:

1779

AN:

41546

American (AMR)

AF:

0.176

AC:

2689

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.241

AC:

836

AN:

3466

East Asian (EAS)

AF:

0.00155

AC:

AN:

5164

South Asian (SAS)

AF:

0.0740

AC:

356

AN:

4814

European-Finnish (FIN)

AF:

0.0648

AC:

687

AN:

10610

Middle Eastern (MID)

AF:

0.218

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.217

AC:

14742

AN:

67958

Other (OTH)

AF:

0.183

AC:

387

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

926

1852

2778

3704

4630

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

234

468

702

936

1170

<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:

0.199

Hom.:

1203

Bravo

AF:

0.148

Asia WGS

AF:

0.0310

AC:

110

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.066

(source)

DANN

Benign

0.37

PhyloP100

-3.1

Mutation Taster

=100/0

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over