rs200742772

Variant names:

• chr8-43122528-A-G
• rs200742772
• NM_032237.5:c.704A>G
• POMK p.Asn235Ser

Your query was ambiguous. Multiple possible variants found:

• chr8-43122528-A-G
• chr8-43122528-A-T

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). BP4_Moderate

The NM_032237.5(POMK):c.704A>G (p.Asn235Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000101 (AC=163) in the gnomAD database across 1,614,058 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000236. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 8.78). Variant has been reported in ClinVar as Uncertain Significance (no review stars).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: POMK NM_032237.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 8.78
• 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: 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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (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.704A>G p.Asn235Ser	missense	Exon 5 of 5	Prot: NP_115613.1 UniProt:
	POMK NM_001277971.2		c.704A>G p.Asn235Ser	missense	Exon 4 of 4	Prot: NP_001264900.1 UniProt:

POMK NM_032237.5

MANE Select

HGVSc / HGVSpc.704A>Gp.Asn235Ser

Exon rankExon 5 of 5

missense

Prot: NP_115613.1UniProt: Q9H5K3

POMK NM_001277971.2

HGVSc / HGVSpc.704A>Gp.Asn235Ser

Exon rankExon 4 of 4

missense

Prot: NP_001264900.1UniProt: Q9H5K3

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	POMK ENST00000331373.10	TSL:2MANE Select	c.704A>G p.Asn235Ser	missense	Exon 5 of 5	Prot: ENSP00000331258.5 UniProt:
	POMK ENST00000676193.1		c.704A>G p.Asn235Ser	missense	Exon 4 of 4	Prot: ENSP00000502774.1 UniProt:
	POMK ENST00000936358.1		c.704A>G p.Asn235Ser	missense	Exon 5 of 6	Prot: ENSP00000606417.1 UniProt:

POMK ENST00000331373.10

TSL:2MANE Select

HGVSc / HGVSpc.704A>Gp.Asn235Ser

Exon rankExon 5 of 5

missense

Prot: ENSP00000331258.5UniProt: Q9H5K3

POMK ENST00000676193.1

HGVSc / HGVSpc.704A>Gp.Asn235Ser

Exon rankExon 4 of 4

missense

Prot: ENSP00000502774.1UniProt: Q9H5K3

POMK ENST00000936358.1

HGVSc / HGVSpc.704A>Gp.Asn235Ser

Exon rankExon 5 of 6

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000723	AC:11	Hom:0	AN:152202	Cov:33
GnomAD2 exomes	AF: 0.000147	AC:37	Hom:	AN:251132	Cov:
GnomAD4 exome	AF: 0.000104	AC:152	Hom:0	AN:1461856	Cov:33
GnomAD4 genome	AF: 0.0000723	AC:11	Hom:0	AN:152202	Cov:33
TOPMed (Bravo)	AF: 0.0000907	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000234	AC:11	Hom:0	AN:47010	Cov:
Local & regional cohorts 2 sources Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	AF: 0.000154	AC:2	Hom:	AN:13006	Cov:
Turkish Variome	AF: 0.00164	AC:11	Hom:0	AN:6708	Cov:

Showing 8 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.00 *	0	9622	0.000192 *	2	10428
BipEx(Bipolar disorder (including schizoaffective))	0.000106	3	28420	0.000104	3	28844
Epi25(Epilepsy)	0.0000953	4	41958	0.000179	12	66888
SCHEMA(Schizophrenia)	0.0000884	10	113098	0.0000945	18	190534

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	-	Inborn genetic diseases (1)
-	1	-	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 12 (1)
-	1	-	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 12;C4015184:Limb-girdle muscular dystrophy due to POMK deficiency (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	19
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.022	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Benign	0.0059
GPN-Star LLR	N/A	-5.0
GPN-Star score	N/A	5.0
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-1.1	T
Mutation Taster	N/A	78/22	polymorphism
MutationAssessor	Benign	1.8	L
PhyloP100	Pathogenic	8.8
popEVE	Benign	-3.1
PrimateAI	Benign	0.38	T
PromoterAI	N/A	0.017	Neutral
PROVEAN	Benign	-1.9	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Benign	0.12
Sift	Benign	0.056	T
Sift4G	Benign	0.19	T
Varity_R	N/A	0.090
VESM-3B	Benign	-7.4

Showing 31 of 31 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.040
SpliceAI score (max)	Benign	0.020	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

Other links and lift over

dbSNP: rs200742772;

hg19: chr8-42977671;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar