2-169584491-G-T

Variant names:

• chr2-169584491-G-T
• rs2276611
• ENST00000462903.6:c.-76G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The ENST00000462903.6(PPIG):​c.-76G>T variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.00000314 in 318,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000031 (0 hom.)
• Consequence: PPIG ENST00000462903.6 5_prime_UTR
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.29
• Publications: 0 publications found

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]

ENSG00000307322 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000462903.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPIG	NM_004792.3	MANE Select	c.-70+1G>T		splice_donor intron	N/A	NP_004783.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPIG	ENST00000462903.6	TSL:1	c.-76G>T		5_prime_UTR	Exon 1 of 12	ENSP00000435987.1
	PPIG	ENST00000260970.8	TSL:1 MANE Select	c.-70+1G>T		splice_donor intron	N/A	ENSP00000260970.3
	PPIG	ENST00000433207.6	TSL:1	c.-70+1G>T		splice_donor intron	N/A	ENSP00000408683.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000314 AC: 1 AN: 318664 Hom.: 0 Cov.: 0 AF XY: 0.00000555 AC XY: 1 AN XY: 180066

African (AFR) AF: 0.00 AC: 0 AN: 8610

American (AMR) AF: 0.00 AC: 0 AN: 27178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10784

East Asian (EAS) AF: 0.00 AC: 0 AN: 9208

South Asian (SAS) AF: 0.0000167 AC: 1 AN: 59736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2784

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 158984

Other (OTH) AF: 0.00 AC: 0 AN: 14324

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Benign	0.29	N
PhyloP100		4.3
GERP RS		5.4
PromoterAI		-0.43	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.85		Position offset: 6
DS_DL_spliceai		1.0		Position offset: -1

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

Other links and lift over

dbSNP: rs2276611; hg19: chr2-170441001;