chr14-77298773-T-G

Variant names:

• chr14-77298773-T-G
• rs886044256
• NM_013382.7:c.924-2A>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_013382.7(POMT2):​c.924-2A>C variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: POMT2 NM_013382.7 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.92
• Publications: 2 publications found

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]

POMT2 Gene-Disease associations (from GenCC):

• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• myopathy caused by variation in POMT2

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• autosomal recessive limb-girdle muscular dystrophy type 2N

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy with cerebellar involvement

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy with intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscle-eye-brain disease

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.03683977 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.3, offset of 24, new splice context is: cctggtgacggtttcttcAGttc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-77298773-T-G is Pathogenic according to our data. Variant chr14-77298773-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 449378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013382.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMT2	NM_013382.7	MANE Select	c.924-2A>C		splice_acceptor intron	N/A	NP_037514.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMT2	ENST00000261534.9	TSL:1 MANE Select	c.924-2A>C		splice_acceptor intron	N/A	ENSP00000261534.4
	POMT2	ENST00000682795.1		c.924-2A>C		splice_acceptor intron	N/A	ENSP00000507574.1
	POMT2	ENST00000682247.1		c.924-2A>C		splice_acceptor intron	N/A	ENSP00000507213.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

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 Pathogenic:2

Mar 26, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in POMT2 are known to be pathogenic (PMID: 15894594). Disruption of this splice site has been observed in several individuals affected with POMT2-related Walker-Warburg Syndrome or POMT2-related lissencephaly (PMID: 18752264, 26495167, 17559086). ClinVar contains an entry for this variant (Variation ID: 449378). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 7 of the POMT2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.

Apr 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2 Pathogenic:2

May 13, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 29, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Apr 08, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: POMT2 c.924-2A>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 246094 control chromosomes (gnomAD). c.924-2A>C has been reported in the literature in individuals affected with Walker-Warburg Syndrome (Manzini_2008, Abumansour_2015). These data indicate that the variant is very likely to be associated with disease. ClinVar contains an entry for this variant (Variation ID: 449378). Based on the evidence outlined above, the variant was classified as pathogenic.

not provided Pathogenic:1

Jun 08, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.924-2 A>C pathogenic splice site variant has been previously reported as a homozygous variant in three fetus' with congenital hydrocephalus in one consanguineous family (Abumansour et al., 2015). This variant destroys the canonical splice acceptor site of intron 7. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subjected to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.924-2 A>C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret c.924-2 A>C as a pathogenic variant.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	0.81
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		5.9
GERP RS		4.3
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.53		Position offset: -26
DS_AL_spliceai		0.99		Position offset: -2

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

Other links and lift over

dbSNP: rs886044256; hg19: chr14-77765116;