NM_013382.7:c.658C>T

Variant names:

• chr14-77301248-G-A
• rs771201662
• NM_013382.7:c.658C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_013382.7(POMT2):​c.658C>T​(p.Pro220Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on 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. P220L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: POMT2 NM_013382.7 missense, splice_region
• Scores: Splicing: ADA: 0.004701
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.79
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.658C>T	p.Pro220Ser	missense splice_region	Exon 6 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.658C>T	p.Pro220Ser	missense splice_region	Exon 6 of 21	ENSP00000261534.4	Q9UKY4-1
	POMT2	ENST00000556326.5	TSL:1	n.*324C>T		splice_region non_coding_transcript_exon	Exon 5 of 6	ENSP00000450630.1	Q9UKY4-2
	POMT2	ENST00000556326.5	TSL:1	n.*324C>T		3_prime_UTR	Exon 5 of 6	ENSP00000450630.1	Q9UKY4-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461848 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

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	Benign	0.18
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	23
DANN	Benign	0.92
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.081	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.4	L
PhyloP100		6.8
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.40
Sift	Benign	0.62	T
Sift4G	Benign	0.56	T
Polyphen		0.040	B
Vest4		0.32
MutPred		0.57		Gain of catalytic residue at W225 (P = 5e-04)
MVP		0.88
MPC		0.13
ClinPred		0.90	D
GERP RS		5.8
PromoterAI		-0.078	Neutral
Varity_R		0.35
gMVP		0.52
Mutation Taster		=43/57	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0047
dbscSNV1_RF	Benign	0.052
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: rs771201662; hg19: chr14-77767591;