22-31291186-C-T

Variant names:

• chr22-31291186-C-T
• rs200641882
• NM_052880.5:c.181G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_052880.5(PIK3IP1):​c.181G>A​(p.Val61Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,546,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V61L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: PIK3IP1 NM_052880.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.391

Genes affected

PIK3IP1 (HGNC:24942): (phosphoinositide-3-kinase interacting protein 1) Enables phosphatidylinositol 3-kinase catalytic subunit binding activity. Involved in negative regulation of phosphatidylinositol 3-kinase activity and negative regulation of phosphatidylinositol 3-kinase signaling. Predicted to be located in plasma membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.008599281).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3IP1	NM_052880.5	c.181G>A	p.Val61Met	missense_variant	Exon 2 of 6	ENST00000215912.10	NP_443112.2
PIK3IP1	NM_001135911.1	c.181G>A	p.Val61Met	missense_variant	Exon 2 of 5		NP_001129383.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3IP1	ENST00000215912.10	c.181G>A	p.Val61Met	missense_variant	Exon 2 of 6	1	NM_052880.5	ENSP00000215912.4
PIK3IP1	ENST00000402249.7	c.181G>A	p.Val61Met	missense_variant	Exon 2 of 5	1		ENSP00000385204.3
PIK3IP1	ENST00000441972.5	c.181G>A	p.Val61Met	missense_variant	Exon 2 of 5	2		ENSP00000415608.1
PIK3IP1	ENST00000443175.1	c.181G>A	p.Val61Met	missense_variant	Exon 2 of 4	4		ENSP00000414227.1

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152198 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000868

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000701 AC: 10 AN: 142750 Hom.: 0 AF XY: 0.0000519 AC XY: 4 AN XY: 77124

Gnomad AFR exome AF: 0.00113

Gnomad AMR exome AF: 0.0000828

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000444

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000179 AC: 25 AN: 1394330 Hom.: 0 Cov.: 38 AF XY: 0.0000174 AC XY: 12 AN XY: 687716

Gnomad4 AFR exome AF: 0.000646

Gnomad4 AMR exome AF: 0.0000849

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000282

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152314 Hom.: 0 Cov.: 34 AF XY: 0.000309 AC XY: 23 AN XY: 74480

Gnomad4 AFR AF: 0.000962

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000849 Hom.: 0

Bravo AF: 0.000272

ESP6500AA AF: 0.000814 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000278 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.181G>A (p.V61M) alteration is located in exon 2 (coding exon 2) of the PIK3IP1 gene. This alteration results from a G to A substitution at nucleotide position 181, causing the valine (V) at amino acid position 61 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.7
DANN	Benign	0.92
DEOGEN2	Benign	0.0063	T;.;.;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.52	T;T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0086	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L;L;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.22	N;N;N;N
REVEL	Benign	0.031
Sift	Benign	0.22	T;T;T;T
Sift4G	Benign	0.17	T;T;T;.
Polyphen		0.24	B;.;P;.
Vest4		0.16
MVP		0.40
MPC		0.40
ClinPred		0.0097	T
GERP RS		1.6
Varity_R		0.041
gMVP		0.39

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: rs200641882; hg19: chr22-31687172; COSMIC: COSV53225086; COSMIC: COSV53225086;