rs12373124

Positions:

• chr17-45846853-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.13

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:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
SPPL2C	NM_175882.3	c.1947T>C	p.His649His	synonymous_variant	1/1	ENST00000329196.7	NP_787078.2
MAPT-AS1	NR_024559.1	n.35-2692A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPPL2C	ENST00000329196.7	c.1947T>C	p.His649His	synonymous_variant	1/1	6	NM_175882.3	ENSP00000332488.5

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21808 AN: 152056 Hom.: 2128 Cov.: 33

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

GnomAD3 exomes AF: 0.145 AC: 36333 AN: 250560 Hom.: 3508 AF XY: 0.149 AC XY: 20132 AN XY: 135564

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 SAS exome AF: 0.0762

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.: 42 AF XY: 0.191 AC XY: 138858 AN XY: 726792

Gnomad4 AFR exome AF: 0.0365

Gnomad4 AMR exome AF: 0.125

Gnomad4 ASJ exome AF: 0.257

Gnomad4 EAS exome AF: 0.000907

Gnomad4 SAS exome AF: 0.0797

Gnomad4 FIN exome AF: 0.0720

Gnomad4 NFE exome AF: 0.222

Gnomad4 OTH exome AF: 0.177

GnomAD4 genome AF: 0.143 AC: 21798 AN: 152174 Hom.: 2126 Cov.: 33 AF XY: 0.134 AC XY: 9977 AN XY: 74412

Gnomad4 AFR AF: 0.0428

Gnomad4 AMR AF: 0.176

Gnomad4 ASJ AF: 0.241

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.0740

Gnomad4 FIN AF: 0.0648

Gnomad4 NFE AF: 0.217

Gnomad4 OTH AF: 0.183

Alfa AF: 0.201 Hom.: 1201

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
DANN	Benign	0.37

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

LitVar

Other links and lift over

dbSNP: rs12373124; hg19: chr17-43924219;