2-201647726-C-G

Position:

• chr2-201647726-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033066.3(MPP4):​c.1684G>C​(p.Val562Leu) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V562I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MPP4 NM_033066.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.84

Genes affected

MPP4 (HGNC:13680): (MAGUK p55 scaffold protein 4) This gene encodes a member of the membrane-associated guanylate kinase (MAGUK) protein family, with an N-terminal PDZ domain, a central src homology 3 region (SH3), and a C-terminal guanylate kinase-like (GUK) domain. The protein is localized to the outer limiting membrane in the retina, and is thought to function in photoreceptor polarity and the organization of specialized intercellular junctions. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15888616).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPP4	NM_033066.3	c.1684G>C	p.Val562Leu	missense_variant	21/22	ENST00000409474.8	NP_149055.2
MPP4	XM_017004620.2	c.1591G>C	p.Val531Leu	missense_variant	17/18		XP_016860109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPP4	ENST00000409474.8	c.1684G>C	p.Val562Leu	missense_variant	21/22	1	NM_033066.3	ENSP00000387278	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Oct 25, 2023

The c.1684G>C (p.V562L) alteration is located in exon 21 (coding exon 20) of the MPP4 gene. This alteration results from a G to C substitution at nucleotide position 1684, causing the valine (V) at amino acid position 562 to be replaced by a leucine (L). 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	0.12
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.027	T;.;T;T;.;T;.;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.25	T;T;T;T;T;T;T;.
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.31	N;N;N;.;.;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.084	T;T;T;.;.;T;T;T
Sift4G	Benign	0.40	T;T;T;T;T;T;T;T
Polyphen		0.0010	B;B;.;.;B;B;B;B
Vest4		0.15
MutPred		0.39		Loss of methylation at K561 (P = 0.0496);.;.;.;.;.;.;.;
MVP		0.47
MPC		0.063
ClinPred		0.60	D
GERP RS		5.7
Varity_R		0.099
gMVP		0.20

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-202512449;