rs138980930

Variant names:

• chr3-43080758-C-T
• rs138980930
• NM_032806.6:c.674G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_032806.6(POMGNT2):​c.674G>A​(p.Arg225Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000369 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R225W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: POMGNT2 NM_032806.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.56
• Publications: 2 publications found

Genes affected

POMGNT2 (HGNC:25902): (protein O-linked mannose N-acetylglucosaminyltransferase 2 (beta 1,4-)) This gene encodes a protein with glycosyltransferase activity although its function is not currently known. [provided by RefSeq, Sep 2012]

POMGNT2 Gene-Disease associations (from GenCC):

• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 8

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
• myopathy caused by variation in POMGNT2

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0106779635).
• BP6: Variant 3-43080758-C-T is Benign according to our data. Variant chr3-43080758-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 262108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00188 (287/152296) while in subpopulation AFR AF = 0.00654 (272/41562). AF 95% confidence interval is 0.00591. There are 0 homozygotes in GnomAd4. There are 130 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032806.6. 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
	POMGNT2	NM_032806.6	MANE Select	c.674G>A	p.Arg225Gln	missense	Exon 2 of 2	NP_116195.2
	POMGNT2	NM_001437285.1		c.674G>A	p.Arg225Gln	missense	Exon 3 of 3	NP_001424214.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMGNT2	ENST00000344697.3	TSL:1 MANE Select	c.674G>A	p.Arg225Gln	missense	Exon 2 of 2	ENSP00000344125.2	Q8NAT1
	POMGNT2	ENST00000441964.1	TSL:4	c.674G>A	p.Arg225Gln	missense	Exon 3 of 3	ENSP00000408992.1	Q8NAT1
	POMGNT2	ENST00000686643.1		c.674G>A	p.Arg225Gln	missense	Exon 4 of 4	ENSP00000509123.1	Q8NAT1

Frequencies

GnomAD3 genomes AF: 0.00188 AC: 286 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00654

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000538 AC: 135 AN: 250876 AF XY: 0.000368

Gnomad AFR exome AF: 0.00608

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000211 AC: 308 AN: 1461782 Hom.: 0 Cov.: 37 AF XY: 0.000184 AC XY: 134 AN XY: 727192

African (AFR) AF: 0.00612 AC: 205 AN: 33480

American (AMR) AF: 0.000246 AC: 11 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86258

European-Finnish (FIN) AF: 0.000506 AC: 27 AN: 53308

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1112012

Other (OTH) AF: 0.000298 AC: 18 AN: 60396

GnomAD4 genome AF: 0.00188 AC: 287 AN: 152296 Hom.: 0 Cov.: 33 AF XY: 0.00175 AC XY: 130 AN XY: 74482

African (AFR) AF: 0.00654 AC: 272 AN: 41562

American (AMR) AF: 0.000523 AC: 8 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000760 Hom.: 2

Bravo AF: 0.00219

ESP6500AA AF: 0.00635 AC: 28

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000708 AC: 86

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	-	1	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 8 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.049
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.6
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.33	N
REVEL	Benign	0.15
Sift	Benign	0.40	T
Sift4G	Benign	0.42	T
Polyphen		0.13	B
Vest4		0.35
MVP		0.70
MPC		0.62
ClinPred		0.016	T
GERP RS		4.8
Varity_R		0.10
gMVP		0.55
Mutation Taster		=97/3	polymorphism

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: rs138980930; hg19: chr3-43122250;