Genetic Variant PAK1IP1:p.Gly6Cys (chr6-10695001-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_017906.3(PAK1IP1):c.16G>T(p.Gly6Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000687 in 1,600,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000060 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

PAK1IP1
NM_017906.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.82

Publications

0 publications found

Variant links:

Genes affected

PAK1IP1 (HGNC:20882): (PAK1 interacting protein 1) Involved in regulation of signal transduction by p53 class mediator and ribosomal large subunit biogenesis. Located in nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

PAK1IP1 links:

C6orf52 (HGNC:20881): (chromosome 6 open reading frame 52)

C6orf52 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.938

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAK1IP1	NM_017906.3 link	c.16G>T	p.Gly6Cys	missense_variant	Exon 1 of 10	ENST00000379568.4	NP_060376.2	Q9NWT1A0A0S2Z5C3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAK1IP1	ENST00000379568.4 link	c.16G>T	p.Gly6Cys	missense_variant	Exon 1 of 10	1	NM_017906.3	ENSP00000368887.3		Q9NWT1
C6orf52	ENST00000503680.1 link	c.-570C>A		upstream_gene_variant		5		ENSP00000421837.1		D6RAP8

Frequencies

GnomAD3 genomes

AF:

0.0000595

AC:

AN:

151176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000288

AC:

AN:

243000

AF XY:

0.0000151

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000697

AC:

101

AN:

1449788

Hom.:

Cov.:

AF XY:

0.0000734

AC XY:

AN XY:

721730

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33450

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41936

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000855

AC:

AN:

1111558

Other (OTH)

AF:

0.0000829

AC:

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000595

AC:

AN:

151176

Hom.:

Cov.:

AF XY:

0.0000543

AC XY:

AN XY:

73710

show subpopulations

African (AFR)

AF:

0.0000244

AC:

AN:

41014

American (AMR)

AF:

0.00

AC:

AN:

15094

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

67938

Other (OTH)

AF:

0.00

AC:

AN:

2066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000153

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 04, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.16G>T (p.G6C) alteration is located in exon 1 (coding exon 1) of the PAK1IP1 gene. This alteration results from a G to T substitution at nucleotide position 16, causing the glycine (G) at amino acid position 6 to be replaced by a cysteine (C). 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

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.42

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.95

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.025

MutationAssessor

Uncertain

2.2

PhyloP100

7.8

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-7.1

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.89

MVP

0.94

MPC

0.65

ClinPred

0.95

GERP RS

5.1

PromoterAI

0.066

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.83

Mutation Taster

=23/77

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

6-10695001-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over