NM_032237.5:c.502A>G

Variant names:

• chr8-43122326-A-G
• rs756014333
• NM_032237.5:c.502A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032237.5(POMK):​c.502A>G​(p.Lys168Glu) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K168Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: POMK NM_032237.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.82
• Publications: 0 publications found

Genes affected

POMK (HGNC:26267): (protein O-mannose kinase) This gene encodes a protein that may be involved in the presentation of the laminin-binding O-linked carbohydrate chain of alpha-dystroglycan (a-DG), which forms transmembrane linkages between the extracellular matrix and the exoskeleton. Some pathogens use this O-linked carbohydrate unit for host entry. Loss of function compound heterozygous mutations in this gene were found in a human patient affected by the Walker-Warburg syndrome (WWS) phenotype. Mice lacking this gene contain misplaced neurons (heterotopia) in some regions of the brain, possibly from defects in neuronal migration. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

POMK Gene-Disease associations (from GenCC):

• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 12

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• congenital muscular dystrophy with cerebellar involvement

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• limb-girdle muscular dystrophy due to POMK deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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=0.3055548).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POMK	NM_032237.5	c.502A>G	p.Lys168Glu	missense_variant	Exon 5 of 5	ENST00000331373.10	NP_115613.1
POMK	NM_001277971.2	c.502A>G	p.Lys168Glu	missense_variant	Exon 4 of 4		NP_001264900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POMK	ENST00000331373.10	c.502A>G	p.Lys168Glu	missense_variant	Exon 5 of 5	2	NM_032237.5	ENSP00000331258.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 12;C4015184:Limb-girdle muscular dystrophy due to POMK deficiency Uncertain:1

Jun 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 168 of the POMK protein (p.Lys168Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with POMK-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;T
Eigen	Benign	-0.032
Eigen_PC	Benign	0.067
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.72	T;.
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.7	L;L
PhyloP100		4.8
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.4	.;N
REVEL	Uncertain	0.34
Sift	Benign	0.10	.;T
Sift4G	Benign	0.092	T;T
Polyphen		0.32	B;B
Vest4		0.28
MutPred		0.52		Loss of ubiquitination at K168 (P = 0.0116);Loss of ubiquitination at K168 (P = 0.0116);
MVP		0.86
MPC		0.15
ClinPred		0.51	D
GERP RS		5.4
PromoterAI		0.0057	Neutral
Varity_R		0.13
gMVP		0.41
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs756014333; hg19: chr8-42977469;