14-77320440-T-G

Variant names:

• chr14-77320440-T-G
• rs746662519
• NM_013382.7:c.242A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_013382.7(POMT2):​c.242A>C​(p.His81Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,394,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. H81R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: POMT2 NM_013382.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.35
• Publications: 1 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925

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.242A>C	p.His81Pro	missense	Exon 1 of 21	NP_037514.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMT2	ENST00000261534.9	TSL:1 MANE Select	c.242A>C	p.His81Pro	missense	Exon 1 of 21	ENSP00000261534.4
	POMT2	ENST00000556326.5	TSL:1	n.242A>C		non_coding_transcript_exon	Exon 1 of 6	ENSP00000450630.1
	POMT2	ENST00000682795.1		c.242A>C	p.His81Pro	missense	Exon 1 of 22	ENSP00000507574.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000682 AC: 1 AN: 146650 AF XY: 0.0000127

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1394252 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 687982

African (AFR) AF: 0.00 AC: 0 AN: 31604

American (AMR) AF: 0.0000560 AC: 2 AN: 35720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25172

East Asian (EAS) AF: 0.00 AC: 0 AN: 35742

South Asian (SAS) AF: 0.00 AC: 0 AN: 79252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078854

Other (OTH) AF: 0.00 AC: 0 AN: 57956

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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 A2;C3150416:Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2;C3150418:Autosomal recessive limb-girdle muscular dystrophy type 2N Uncertain:1

Aug 13, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine with proline at codon 81 of the POMT2 protein (p.His81Pro). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and proline. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with clinical features of POMT2-related conditions (Invitae). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.76	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		6.3
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.98	D
Vest4		0.71
MutPred		0.71		Gain of catalytic residue at W84 (P = 0)
MVP		0.93
MPC		0.56
ClinPred		0.99	D
GERP RS		5.2
PromoterAI		0.031	Neutral
Varity_R		0.89
gMVP		0.95
Mutation Taster		=32/68	disease causing

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: rs746662519; hg19: chr14-77786783;