chr7-24650509-A-C

Position:

• chr7-24650509-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000222644.10(PALS2):​c.448A>C​(p.Asn150His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: PALS2 ENST00000222644.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.94

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35780773).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALS2	NM_001303037.2	c.448A>C	p.Asn150His	missense_variant	5/12	ENST00000222644.10	NP_001289966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALS2	ENST00000222644.10	c.448A>C	p.Asn150His	missense_variant	5/12	1	NM_001303037.2	ENSP00000222644.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2022

The c.448A>C (p.N150H) alteration is located in exon 6 (coding exon 4) of the MPP6 gene. This alteration results from a A to C substitution at nucleotide position 448, causing the asparagine (N) at amino acid position 150 to be replaced by a histidine (H). 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	0.091
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	T;T;T;T;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;.;D;D;D
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.36	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	.;L;.;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.3	N;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.045	D;D;D;D;T
Sift4G	Benign	0.082	T;T;T;T;T
Polyphen		0.84	.;P;.;P;.
Vest4		0.33, 0.30, 0.29
MutPred		0.41		Gain of catalytic residue at L152 (P = 0.0623);Gain of catalytic residue at L152 (P = 0.0623);.;Gain of catalytic residue at L152 (P = 0.0623);Gain of catalytic residue at L152 (P = 0.0623);
MVP		0.59
MPC		1.2
ClinPred		0.91	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.20
gMVP		0.50

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-24690128;