chr7-24687474-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000222644.10(PALS2):​c.1483C>T​(p.Arg495Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,458,374 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

PALS2
ENST00000222644.10 missense

Scores

7
6
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.22
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PALS2NM_001303037.2 linkuse as main transcriptc.1483C>T p.Arg495Trp missense_variant 12/12 ENST00000222644.10 NP_001289966.1 Q9NZW5A0A024RA25

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PALS2ENST00000222644.10 linkuse as main transcriptc.1483C>T p.Arg495Trp missense_variant 12/121 NM_001303037.2 ENSP00000222644.4 Q9NZW5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000162
AC:
4
AN:
247484
Hom.:
0
AF XY:
0.0000224
AC XY:
3
AN XY:
133820
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000300
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000337
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000178
AC:
26
AN:
1458374
Hom.:
0
Cov.:
30
AF XY:
0.0000179
AC XY:
13
AN XY:
725436
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000682
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000253
Gnomad4 SAS exome
AF:
0.0000234
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000171
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000930
Hom.:
0
Bravo
AF:
0.0000264

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 20, 2024The c.1483C>T (p.R495W) alteration is located in exon 13 (coding exon 11) of the MPP6 gene. This alteration results from a C to T substitution at nucleotide position 1483, causing the arginine (R) at amino acid position 495 to be replaced by a tryptophan (W). 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
0.77
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.10
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Benign
0.18
T;T;T
Eigen
Pathogenic
0.74
Eigen_PC
Pathogenic
0.72
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Pathogenic
0.99
.;D;D
M_CAP
Benign
0.026
D
MetaRNN
Uncertain
0.72
D;D;D
MetaSVM
Benign
-0.62
T
MutationAssessor
Pathogenic
3.3
M;.;M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.84
D
PROVEAN
Uncertain
-3.5
D;D;D
REVEL
Uncertain
0.29
Sift
Benign
0.18
T;T;T
Sift4G
Benign
0.18
T;T;T
Polyphen
1.0
D;.;D
Vest4
0.76
MVP
0.78
MPC
1.5
ClinPred
0.97
D
GERP RS
5.0
Varity_R
0.45
gMVP
0.83

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.18
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs894818719; hg19: chr7-24727093; COSMIC: COSV56035271; API