14-77320433-C-G

Variant names:

• chr14-77320433-C-G
• rs961440747
• NM_013382.7:c.248+1G>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_013382.7(POMT2):​c.248+1G>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000287 in 1,394,328 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: POMT2 NM_013382.7 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.26
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• 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 14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.19973369 fraction of the gene.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-77320433-C-G is Pathogenic according to our data. Variant chr14-77320433-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 579369.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMT2	NM_013382.7	MANE Select	c.248+1G>C		splice_donor intron	N/A	NP_037514.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMT2	ENST00000261534.9	TSL:1 MANE Select	c.248+1G>C		splice_donor intron	N/A	ENSP00000261534.4	Q9UKY4-1
	POMT2	ENST00000556326.5	TSL:1	n.248+1G>C		splice_donor intron	N/A	ENSP00000450630.1	Q9UKY4-2
	POMT2	ENST00000682795.1		c.248+1G>C		splice_donor intron	N/A	ENSP00000507574.1	A0A804HJN3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000136 AC: 2 AN: 147030 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: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000287 AC: 4 AN: 1394328 Hom.: 0 Cov.: 30 AF XY: 0.00000436 AC XY: 3 AN XY: 687998

African (AFR) AF: 0.00 AC: 0 AN: 31600

American (AMR) AF: 0.0000280 AC: 1 AN: 35724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25170

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 79246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1078834

Other (OTH) AF: 0.0000173 AC: 1 AN: 57956

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2 (1)
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
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		6.3
GERP RS		5.2
PromoterAI		-0.60	Under-expression
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: 1

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

Other links and lift over

dbSNP: rs961440747; hg19: chr14-77786776;