Genetic Variant POMK:p.Asn235Ile (chr8-43122528-AC-TA) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_032237.5(POMK):c.704_705delACinsTA (p.Asn235Ile) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 8.78). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.N235S: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 474196)

Frequency

Genomes: not found (cov: 33)

Consequence

POMK
NM_032237.5 missense

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.78

Publications

0 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, PanelApp Australia, G2P
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
anterior segment dysgenesis
Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia

POMK links:

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new If you want to explore the variant's impact on the transcript NM_032237.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Show applied only (1)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_032237.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	POMK NM_032237.5	MANE Select	c.704_705delACinsTA p.Asn235Ile	missense	N/A	Prot: NP_115613.1 UniProt: Q9H5K3
	POMK NM_001277971.2		c.704_705delACinsTA p.Asn235Ile	missense	N/A	Prot: NP_001264900.1 UniProt: Q9H5K3

POMK NM_032237.5

MANE Select

HGVSc / HGVSpc.704_705delACinsTAp.Asn235Ile

Exon rankN/A

missense

Prot: NP_115613.1UniProt: Q9H5K3

POMK NM_001277971.2

HGVSc / HGVSpc.704_705delACinsTAp.Asn235Ile

Exon rankN/A

missense

Prot: NP_001264900.1UniProt: Q9H5K3

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
POMK ENST00000331373.10	TSL:2MANE Select	c.704_705delACinsTA p.Asn235Ile	missense	N/A	Prot: ENSP00000331258.5 UniProt: Q9H5K3
POMK ENST00000676193.1		c.704_705delACinsTA p.Asn235Ile	missense	N/A	Prot: ENSP00000502774.1 UniProt: Q9H5K3
POMK ENST00000936358.1		c.704_705delACinsTA p.Asn235Ile	missense	N/A	Prot: ENSP00000606417.1 UniProt: Q9H5K3

POMK ENST00000331373.10

TSL:2MANE Select

HGVSc / HGVSpc.704_705delACinsTAp.Asn235Ile

Exon rankN/A

missense

Prot: ENSP00000331258.5UniProt: Q9H5K3

POMK ENST00000676193.1

HGVSc / HGVSpc.704_705delACinsTAp.Asn235Ile

Exon rankN/A

missense

Prot: ENSP00000502774.1UniProt: Q9H5K3

POMK ENST00000936358.1

HGVSc / HGVSpc.704_705delACinsTAp.Asn235Ile

Exon rankN/A

missense

Prot: ENSP00000606417.1UniProt: Q9H5K3

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	8.8

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence