NM_013382.7:c.1881G>A

Variant names:

• chr14-77279833-C-T
• rs146588608
• NM_013382.7:c.1881G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_013382.7(POMT2):​c.1881G>A​(p.Ala627Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 1,613,352 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (10 hom.)
• Consequence: POMT2 NM_013382.7 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.433
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.021).
• BP6: Variant 14-77279833-C-T is Benign according to our data. Variant chr14-77279833-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194863.
• BP7: Synonymous conserved (PhyloP=-0.433 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00171 (260/152218) while in subpopulation SAS AF = 0.00539 (26/4826). AF 95% confidence interval is 0.00378. There are 1 homozygotes in GnomAd4. There are 123 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

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.1881G>A	p.Ala627Ala	synonymous	Exon 18 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.1881G>A	p.Ala627Ala	synonymous	Exon 18 of 21	ENSP00000261534.4	Q9UKY4-1
	POMT2	ENST00000682795.1		c.1881G>A	p.Ala627Ala	synonymous	Exon 18 of 22	ENSP00000507574.1	A0A804HJN3
	POMT2	ENST00000923942.1		c.1881G>A	p.Ala627Ala	synonymous	Exon 18 of 22	ENSP00000594001.1

Frequencies

GnomAD3 genomes AF: 0.00171 AC: 260 AN: 152100 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00276

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00207 AC: 515 AN: 249220 AF XY: 0.00235

Gnomad AFR exome AF: 0.000312

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.000499

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.000282

Gnomad NFE exome AF: 0.00240

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.00275 AC: 4020 AN: 1461134 Hom.: 10 Cov.: 33 AF XY: 0.00291 AC XY: 2116 AN XY: 726830

African (AFR) AF: 0.000538 AC: 18 AN: 33472

American (AMR) AF: 0.000470 AC: 21 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26128

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39680

South Asian (SAS) AF: 0.00647 AC: 558 AN: 86178

European-Finnish (FIN) AF: 0.000679 AC: 36 AN: 52986

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.00289 AC: 3210 AN: 1111880

Other (OTH) AF: 0.00250 AC: 151 AN: 60364

GnomAD4 genome AF: 0.00171 AC: 260 AN: 152218 Hom.: 1 Cov.: 32 AF XY: 0.00165 AC XY: 123 AN XY: 74424

African (AFR) AF: 0.000361 AC: 15 AN: 41530

American (AMR) AF: 0.000784 AC: 12 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.000581 AC: 3 AN: 5162

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4826

European-Finnish (FIN) AF: 0.000848 AC: 9 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00276 AC: 188 AN: 67998

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00182 Hom.: 0

Bravo AF: 0.00148

Asia WGS AF: 0.00318 AC: 12 AN: 3478

EpiCase AF: 0.00245

EpiControl AF: 0.00202

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2N (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_noAF	Benign	-0.61
CADD	Benign	1.8
DANN	Benign	0.49
PhyloP100		-0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs146588608; hg19: chr14-77746176;