rs2276611

Positions:

• chr2-169584491-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3 BA1

The NM_004792.3(PPIG):​c.-70+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.161 in 470,750 control chromosomes in the GnomAD database, including 6,741 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.15 (1870 hom., cov: 32)
  • Exomes 𝑓: 0.17 (4871 hom.)
• Consequence: PPIG NM_004792.3 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.29

Genes affected

PPIG (HGNC:14650): (peptidylprolyl isomerase G) Enables cyclosporin A binding activity and peptidyl-prolyl cis-trans isomerase activity. Involved in protein peptidyl-prolyl isomerization. Located in cytosol and nuclear speck. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 6: BayesDel_noAF, Cadd, dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, Eigen [when BayesDel_addAF, MutationTaster was below the threshold]
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.246 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPIG	NM_004792.3	c.-70+1G>A		splice_donor_variant		ENST00000260970.8	NP_004783.2
PPIG	XM_017005302.3	c.-70+1G>A		splice_donor_variant			XP_016860791.1
PPIG	XM_005246967.2	c.-76G>A		5_prime_UTR_variant	1/14		XP_005247024.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPIG	ENST00000260970.8	c.-70+1G>A		splice_donor_variant		1	NM_004792.3	ENSP00000260970	P1

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23228 AN: 152064 Hom.: 1859 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.0827

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.258

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.141

GnomAD3 exomes AF: 0.169 AC: 25547 AN: 151274 Hom.: 2437 AF XY: 0.172 AC XY: 13977 AN XY: 81296

Gnomad AFR exome AF: 0.181

Gnomad AMR exome AF: 0.203

Gnomad ASJ exome AF: 0.0821

Gnomad EAS exome AF: 0.199

Gnomad SAS exome AF: 0.248

Gnomad FIN exome AF: 0.173

Gnomad NFE exome AF: 0.129

Gnomad OTH exome AF: 0.144

GnomAD4 exome AF: 0.165 AC: 52570 AN: 318566 Hom.: 4871 Cov.: 0 AF XY: 0.171 AC XY: 30723 AN XY: 180010

Gnomad4 AFR exome AF: 0.178

Gnomad4 AMR exome AF: 0.206

Gnomad4 ASJ exome AF: 0.0812

Gnomad4 EAS exome AF: 0.207

Gnomad4 SAS exome AF: 0.245

Gnomad4 FIN exome AF: 0.175

Gnomad4 NFE exome AF: 0.132

Gnomad4 OTH exome AF: 0.142

GnomAD4 genome AF: 0.153 AC: 23274 AN: 152184 Hom.: 1870 Cov.: 32 AF XY: 0.155 AC XY: 11557 AN XY: 74390

Gnomad4 AFR AF: 0.175

Gnomad4 AMR AF: 0.148

Gnomad4 ASJ AF: 0.0827

Gnomad4 EAS AF: 0.212

Gnomad4 SAS AF: 0.258

Gnomad4 FIN AF: 0.176

Gnomad4 NFE AF: 0.129

Gnomad4 OTH AF: 0.142

Alfa AF: 0.134 Hom.: 2416

Bravo AF: 0.151

TwinsUK AF: 0.122 AC: 451

ALSPAC AF: 0.136 AC: 526

ExAC AF: 0.158 AC: 3221

Asia WGS AF: 0.253 AC: 881 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Benign	0.27	N
MutationTaster	Benign	3.2e-28	P;P;P;P
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.90		Position offset: 6
DS_DL_spliceai		0.98		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2276611; hg19: chr2-170441001;