rs2233683

Variant names:

• chr19-9838726-C-A
• rs2233683
• NM_006221.4:c.271+78C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-9838726-C-A
• chr19-9838726-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006221.4(PIN1):​c.271+78C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000946 in 1,057,182 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 9.5e-7 (0 hom.)
• Consequence: PIN1 NM_006221.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.08
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIN1	NM_006221.4	c.271+78C>A		intron_variant	Intron 2 of 3	ENST00000247970.9	NP_006212.1
PIN1	NR_038422.3	n.351+78C>A		intron_variant	Intron 3 of 4
PIN1	NR_038830.2	n.351+78C>A		intron_variant	Intron 3 of 5
PIN1	XM_011528068.3	c.286+78C>A		intron_variant	Intron 4 of 5		XP_011526370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIN1	ENST00000247970.9	c.271+78C>A		intron_variant	Intron 2 of 3	1	NM_006221.4	ENSP00000247970.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.46e-7 AC: 1 AN: 1057182 Hom.: 0 AF XY: 0.00000190 AC XY: 1 AN XY: 527284

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25154

American (AMR) AF: 0.00 AC: 0 AN: 32510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20614

East Asian (EAS) AF: 0.00 AC: 0 AN: 33820

South Asian (SAS) AF: 0.00 AC: 0 AN: 68044

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3688

European-Non Finnish (NFE) AF: 0.00000126 AC: 1 AN: 794484

Other (OTH) AF: 0.00 AC: 0 AN: 46444

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.0
DANN	Benign	0.54
PhyloP100		-1.1

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: rs2233683; hg19: chr19-9949402;