dbSNP rs781197516: PALS2:p.Thr9Lys (chr7-24623693-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001303037.2(PALS2):c.26C>A(p.Thr9Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T9R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PALS2
NM_001303037.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.65

Publications

5 publications found

Variant links:

Genes affected

PALS2 (HGNC:18167): (protein associated with LIN7 2, MAGUK p55 family member) Members of the peripheral membrane-associated guanylate kinase (MAGUK) family function in tumor suppression and receptor clustering by forming multiprotein complexes containing distinct sets of transmembrane, cytoskeletal, and cytoplasmic signaling proteins. All MAGUKs contain a PDZ-SH3-GUK core and are divided into 4 subfamilies, DLG-like (see DLG1; MIM 601014), ZO1-like (see TJP1; MIM 601009), p55-like (see MPP1; MIM 305360), and LIN2-like (see CASK; MIM 300172), based on their size and the presence of additional domains. MPP6 is a member of the p55-like MAGUK subfamily (Tseng et al., 2001 [PubMed 11311936]).[supplied by OMIM, Mar 2008]

PALS2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1559819).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALS2	NM_001303037.2 link	c.26C>A	p.Thr9Lys	missense_variant	Exon 2 of 12	ENST00000222644.10	NP_001289966.1	Q9NZW5A0A024RA25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALS2	ENST00000222644.10 link	c.26C>A	p.Thr9Lys	missense_variant	Exon 2 of 12	1	NM_001303037.2	ENSP00000222644.4		Q9NZW5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

239718

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1447082

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719908

African (AFR)

AF:

0.00

AC:

AN:

32612

American (AMR)

AF:

0.00

AC:

AN:

40960

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25522

East Asian (EAS)

AF:

0.00

AC:

AN:

39524

South Asian (SAS)

AF:

0.00

AC:

AN:

83238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53262

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106486

Other (OTH)

AF:

0.00

AC:

AN:

59774

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.16

T;T;T;T;T

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.056

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.77

T;.;T;T;T

M_CAP

Benign

0.0035

MetaRNN

Benign

0.16

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.92

.;N;N;.;.

PhyloP100

2.6

PrimateAI

Uncertain

0.61

PROVEAN

Benign

0.27

N;N;N;N;.

REVEL

Benign

0.052

Sift

Benign

0.81

T;T;T;T;.

Sift4G

Benign

0.76

T;T;T;T;T

Polyphen

0.0030

.;B;B;.;.

Vest4

0.26, 0.28, 0.28

MutPred

0.45

Gain of ubiquitination at T9 (P = 0.0054);Gain of ubiquitination at T9 (P = 0.0054);Gain of ubiquitination at T9 (P = 0.0054);Gain of ubiquitination at T9 (P = 0.0054);Gain of ubiquitination at T9 (P = 0.0054);

MVP

0.36

MPC

0.67

ClinPred

0.77

GERP RS

4.5

PromoterAI

-0.029

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.17

gMVP

0.35

Mutation Taster

=67/33

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over