rs587780422

Positions:

• chr14-77298684-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_013382.7(POMT2):​c.1006+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000308 in 1,461,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: POMT2 NM_013382.7 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:5
• Conservation: PhyloP100: 7.39

Genes affected

POMT2 (HGNC:19743): (protein O-mannosyltransferase 2) The protein encoded by this gene is an O-mannosyltransferase that requires interaction with the product of the POMT1 gene for enzymatic function. The encoded protein is found in the membrane of the endoplasmic reticulum. Defects in this gene are a cause of Walker-Warburg syndrome (WWS).[provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 14-77298684-C-T is Pathogenic according to our data. Variant chr14-77298684-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130015.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=5, Likely_pathogenic=2}. Variant chr14-77298684-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POMT2	NM_013382.7	c.1006+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000261534.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POMT2	ENST00000261534.9	c.1006+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_013382.7	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 250594 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135404

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000308 AC: 45 AN: 1461466 Hom.: 0 Cov.: 31 AF XY: 0.0000344 AC XY: 25 AN XY: 726960

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000405

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2;C3150416:Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2;C3150418:Autosomal recessive limb-girdle muscular dystrophy type 2N Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 01, 2021	This sequence change falls in intron 8 of the POMT2 gene. It does not directly change the encoded amino acid sequence of the POMT2 protein. It affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs587780422, ExAC 0.005%). This variant has been observed in individual(s) with muscular dystrophy-dystroglycanopathy (PMID: 18752264). ClinVar contains an entry for this variant (Variation ID: 130015). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Dec 13, 2022	The inherited c.1006+5G>A variant identified in the POMT2 gene is a non-canonical splice region variant at the +5 position within intron 8/20. The c.1006+5G>A variant is observed in 9 alleles (~0.0012% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. In silico splicing algorithms unanimously predict this variant to probably affect splicing (spliceAI=0.98, TraP=0.936, >99.9% score-percentile, VarSEAK class 5). The c.1006+5G>A variant is reported in ClinVar as both a Variant of Uncertain Significance (n=3) and as Likely Pathogenic (n=1) (VarID:130015). This variant has been reported in a single individual in the literature with suspected Walker Warburg Syndrome, in trans with a synonymous variant also hypothesized to alter splicing, however functional studies were not performed for either variant in that individual, leaving uncertainty regarding the clinical relevance of those variants [PMID:18752264]. Given the available evidence, the inherited c.1006+5G>A variant identified in the POMT2 gene is currently classified as a Variant of Uncertain Significance. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 29, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 18, 2017	The c.1006+5 G>A variant has been reported previously in an individual with Walker-Warburg syndrome who had a second POMT2 variant identified; however, parental studies were not performed (Manzini et al., 2008). The c.1006+5 G>A variant is observed in 5/111,398 (0.004%) alleles from individuals of European background (Lek et al., 2016). The c.1006+5 G>A variant is predicted to destroy the natural splice donor site in intron 8. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Autosomal recessive limb-girdle muscular dystrophy type 2N Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 17, 2014

- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 29, 2023

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 23, 2023

Variant summary: POMT2 c.1006+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. One computational tool predicts a significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2e-05 in 250594 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1006+5G>A has been reported in the literature in individuals affected with Walker-Warburg syndrome. These report does not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	33
DANN	Uncertain	0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.73		Position offset: -21
DS_DL_spliceai		0.98		Position offset: 5

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

Publications

LitVar

Other links and lift over

dbSNP: rs587780422; hg19: chr14-77765027;