14-77291380-C-G

Variant names:

• chr14-77291380-C-G
• rs267606965
• NM_013382.7:c.1117G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_013382.7(POMT2):​c.1117G>C​(p.Val373Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000711 in 1,406,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. V373F) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: POMT2 NM_013382.7 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.92
• Publications: 0 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-77291380-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3226.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMT2	NM_013382.7	MANE Select	c.1117G>C	p.Val373Leu	missense splice_region	Exon 10 of 21	NP_037514.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMT2	ENST00000261534.9	TSL:1 MANE Select	c.1117G>C	p.Val373Leu	missense splice_region	Exon 10 of 21	ENSP00000261534.4	Q9UKY4-1
	POMT2	ENST00000682795.1		c.1117G>C	p.Val373Leu	missense splice_region	Exon 10 of 22	ENSP00000507574.1	A0A804HJN3
	POMT2	ENST00000923942.1		c.1117G>C	p.Val373Leu	missense splice_region	Exon 10 of 22	ENSP00000594001.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 7.11e-7 AC: 1 AN: 1406978 Hom.: 0 Cov.: 33 AF XY: 0.00000145 AC XY: 1 AN XY: 691422

African (AFR) AF: 0.00 AC: 0 AN: 32618

American (AMR) AF: 0.00 AC: 0 AN: 41552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25316

East Asian (EAS) AF: 0.00 AC: 0 AN: 37712

South Asian (SAS) AF: 0.00 AC: 0 AN: 82212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1074110

Other (OTH) AF: 0.0000173 AC: 1 AN: 57838

GnomAD4 genome Cov.: 25

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	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 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		4.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.82
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.015	D
Polyphen		0.98	D
Vest4		0.79
MutPred		0.78		Gain of catalytic residue at R369 (P = 0.0014)
MVP		0.94
MPC		0.44
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.90
gMVP		0.66
Mutation Taster		=32/68	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.090		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: rs267606965; hg19: chr14-77757723;