Genetic Variant PALS2:p.Lys102Glu (chr7-24649645-A-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001303037.2(PALS2):c.304A>G(p.Lys102Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PALS2
NM_001303037.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.07

Publications

0 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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30848992).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALS2	NM_001303037.2 link	c.304A>G	p.Lys102Glu	missense_variant	Exon 4 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.304A>G	p.Lys102Glu	missense_variant	Exon 4 of 12	1	NM_001303037.2	ENSP00000222644.4		Q9NZW5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000403

AC:

AN:

247886

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000297

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

AF:

0.00000137

AC:

AN:

1458346

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725416

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33248

American (AMR)

AF:

0.0000226

AC:

AN:

44266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26062

East Asian (EAS)

AF:

0.00

AC:

AN:

39418

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85550

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110504

Other (OTH)

AF:

0.00

AC:

AN:

60196

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

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 12, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.304A>G (p.K102E) alteration is located in exon 5 (coding exon 3) of the MPP6 gene. This alteration results from a A to G substitution at nucleotide position 304, causing the lysine (K) at amino acid position 102 to be replaced by a glutamic acid (E). 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

0.57

BayesDel_addAF

Benign

-0.014

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

T;T;T;T

Eigen

Benign

0.19

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.86

D;.;T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.31

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

.;L;L;.

PhyloP100

9.1

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.95

N;N;N;N

REVEL

Benign

0.16

Sift

Benign

0.070

T;T;T;T

Sift4G

Benign

0.19

T;T;T;T

Polyphen

0.026

.;B;B;.

Vest4

0.69, 0.68

MutPred

0.47

Loss of methylation at K102 (P = 2e-04);Loss of methylation at K102 (P = 2e-04);Loss of methylation at K102 (P = 2e-04);Loss of methylation at K102 (P = 2e-04);

MVP

0.71

MPC

0.85

ClinPred

0.43

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.71

Mutation Taster

=40/60

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

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chr7-24649645-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over