rs2233682

Variant names:

• chr19-9838476-G-A
• rs2233682
• NM_006221.4:c.99G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_006221.4(PIN1):​c.99G>A​(p.Gln33Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0205 in 1,609,254 control chromosomes in the GnomAD database, including 1,662 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 0.061 (678 hom., cov: 32)
  • Exomes 𝑓: 0.016 (984 hom.)
• Consequence: PIN1 NM_006221.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.745
• Publications: 18 publications found

Genes affected

PIN1 (HGNC:8988): (peptidylprolyl cis/trans isomerase, NIMA-interacting 1) Peptidyl-prolyl cis/trans isomerases (PPIases) catalyze the cis/trans isomerization of peptidyl-prolyl peptide bonds. This gene encodes one of the PPIases, which specifically binds to phosphorylated ser/thr-pro motifs to catalytically regulate the post-phosphorylation conformation of its substrates. The conformational regulation catalyzed by this PPIase has a profound impact on key proteins involved in the regulation of cell growth, genotoxic and other stress responses, the immune response, induction and maintenance of pluripotency, germ cell development, neuronal differentiation, and survival. This enzyme also plays a key role in the pathogenesis of Alzheimer's disease and many cancers. Multiple alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Jun 2011]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP7: Synonymous conserved (PhyloP=0.745 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006221.4. 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
	PIN1	NM_006221.4	MANE Select	c.99G>A	p.Gln33Gln	synonymous	Exon 2 of 4	NP_006212.1
	PIN1	NR_038422.3		n.179G>A		non_coding_transcript_exon	Exon 3 of 5
	PIN1	NR_038830.2		n.179G>A		non_coding_transcript_exon	Exon 3 of 6

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIN1	ENST00000247970.9	TSL:1 MANE Select	c.99G>A	p.Gln33Gln	synonymous	Exon 2 of 4	ENSP00000247970.5
	PIN1	ENST00000380889.6	TSL:1	n.1132G>A		non_coding_transcript_exon	Exon 3 of 6
	PIN1	ENST00000588695.5	TSL:2	c.99G>A	p.Gln33Gln	synonymous	Exon 2 of 5	ENSP00000466962.1

Frequencies

GnomAD3 genomes AF: 0.0613 AC: 9336 AN: 152188 Hom.: 674 Cov.: 32

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0721

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.0283

Gnomad SAS AF: 0.0370

Gnomad FIN AF: 0.0132

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00611

Gnomad OTH AF: 0.0590

GnomAD2 exomes AF: 0.0372 AC: 8939 AN: 240412 AF XY: 0.0321

Gnomad AFR exome AF: 0.174

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.0197

Gnomad EAS exome AF: 0.0254

Gnomad FIN exome AF: 0.0105

Gnomad NFE exome AF: 0.00632

Gnomad OTH exome AF: 0.0299

GnomAD4 exome AF: 0.0162 AC: 23650 AN: 1456948 Hom.: 984 Cov.: 31 AF XY: 0.0159 AC XY: 11532 AN XY: 724344

African (AFR) AF: 0.179 AC: 5982 AN: 33442

American (AMR) AF: 0.101 AC: 4431 AN: 43680

Ashkenazi Jewish (ASJ) AF: 0.0204 AC: 530 AN: 25952

East Asian (EAS) AF: 0.0346 AC: 1369 AN: 39512

South Asian (SAS) AF: 0.0393 AC: 3342 AN: 85136

European-Finnish (FIN) AF: 0.0108 AC: 571 AN: 52980

Middle Eastern (MID) AF: 0.0400 AC: 212 AN: 5300

European-Non Finnish (NFE) AF: 0.00512 AC: 5688 AN: 1110732

Other (OTH) AF: 0.0253 AC: 1525 AN: 60214

GnomAD4 genome AF: 0.0615 AC: 9363 AN: 152306 Hom.: 678 Cov.: 32 AF XY: 0.0612 AC XY: 4556 AN XY: 74490

African (AFR) AF: 0.173 AC: 7181 AN: 41548

American (AMR) AF: 0.0727 AC: 1112 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3470

East Asian (EAS) AF: 0.0282 AC: 146 AN: 5178

South Asian (SAS) AF: 0.0365 AC: 176 AN: 4828

European-Finnish (FIN) AF: 0.0132 AC: 140 AN: 10630

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.00613 AC: 417 AN: 68040

Other (OTH) AF: 0.0588 AC: 124 AN: 2108

Alfa AF: 0.0345 Hom.: 206

Bravo AF: 0.0721

Asia WGS AF: 0.0550 AC: 190 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.0
DANN	Benign	0.68
PhyloP100		0.74
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2233682; hg19: chr19-9949152; COSMIC: COSV56113416; COSMIC: COSV56113416;