rs2292487

Variant names:

• chr1-46194623-T-C
• rs2292487
• NM_017739.4:c.681A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_017739.4(POMGNT1):​c.681A>G​(p.Lys227Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 1,613,968 control chromosomes in the GnomAD database, including 103,172 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.35 (9438 hom., cov: 33)
  • Exomes 𝑓: 0.35 (93734 hom.)
• Consequence: POMGNT1 NM_017739.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 0.397
• Publications: 38 publications found

Genes affected

POMGNT1 (HGNC:19139): (protein O-linked mannose N-acetylglucosaminyltransferase 1 (beta 1,2-)) This gene encodes a type II transmembrane protein that resides in the Golgi apparatus. It participates in O-mannosyl glycosylation and is specific for alpha linked terminal mannose. Mutations in this gene may be associated with muscle-eye-brain disease and several congenital muscular dystrophies. Alternatively spliced transcript variants that encode different protein isoforms have been described. [provided by RefSeq, Feb 2014]

TSPAN1 (HGNC:20657): (tetraspanin 1) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029520392).
• BP6: Variant 1-46194623-T-C is Benign according to our data. Variant chr1-46194623-T-C is described in ClinVar as Benign. ClinVar VariationId is 95761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.397 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.419 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017739.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMGNT1	NM_017739.4	MANE Select	c.681A>G	p.Lys227Lys	synonymous	Exon 8 of 22	NP_060209.4
	POMGNT1	NM_001243766.2		c.681A>G	p.Lys227Lys	synonymous	Exon 8 of 23	NP_001230695.2
	POMGNT1	NM_001410783.1		c.681A>G	p.Lys227Lys	synonymous	Exon 8 of 22	NP_001397712.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMGNT1	ENST00000371984.8	TSL:1 MANE Select	c.681A>G	p.Lys227Lys	synonymous	Exon 8 of 22	ENSP00000361052.3
	POMGNT1	ENST00000371992.1	TSL:2	c.681A>G	p.Lys227Lys	synonymous	Exon 8 of 23	ENSP00000361060.1
	POMGNT1	ENST00000692369.1		c.681A>G	p.Lys227Lys	synonymous	Exon 8 of 22	ENSP00000508453.1

Frequencies

GnomAD3 genomes AF: 0.349 AC: 53060 AN: 151964 Hom.: 9428 Cov.: 33

Gnomad AFR AF: 0.350

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.434

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.353

Gnomad OTH AF: 0.350

GnomAD2 exomes AF: 0.355 AC: 89316 AN: 251468 AF XY: 0.358

Gnomad AFR exome AF: 0.347

Gnomad AMR exome AF: 0.389

Gnomad ASJ exome AF: 0.306

Gnomad EAS exome AF: 0.145

Gnomad FIN exome AF: 0.392

Gnomad NFE exome AF: 0.353

Gnomad OTH exome AF: 0.352

GnomAD4 exome AF: 0.354 AC: 518207 AN: 1461886 Hom.: 93734 Cov.: 95 AF XY: 0.358 AC XY: 260087 AN XY: 727244

African (AFR) AF: 0.361 AC: 12070 AN: 33480

American (AMR) AF: 0.388 AC: 17347 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 8042 AN: 26136

East Asian (EAS) AF: 0.157 AC: 6229 AN: 39700

South Asian (SAS) AF: 0.450 AC: 38779 AN: 86256

European-Finnish (FIN) AF: 0.395 AC: 21087 AN: 53418

Middle Eastern (MID) AF: 0.381 AC: 2197 AN: 5768

European-Non Finnish (NFE) AF: 0.352 AC: 391774 AN: 1112008

Other (OTH) AF: 0.342 AC: 20682 AN: 60396

GnomAD4 genome AF: 0.349 AC: 53131 AN: 152082 Hom.: 9438 Cov.: 33 AF XY: 0.351 AC XY: 26109 AN XY: 74354

African (AFR) AF: 0.350 AC: 14509 AN: 41478

American (AMR) AF: 0.362 AC: 5541 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 1087 AN: 3468

East Asian (EAS) AF: 0.160 AC: 827 AN: 5174

South Asian (SAS) AF: 0.435 AC: 2096 AN: 4822

European-Finnish (FIN) AF: 0.384 AC: 4060 AN: 10572

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.353 AC: 23994 AN: 67964

Other (OTH) AF: 0.353 AC: 745 AN: 2112

Alfa AF: 0.353 Hom.: 10884

Bravo AF: 0.343

TwinsUK AF: 0.340 AC: 1260

ALSPAC AF: 0.348 AC: 1342

ESP6500AA AF: 0.351 AC: 1548

ESP6500EA AF: 0.349 AC: 3000

ExAC AF: 0.355 AC: 43071

Asia WGS AF: 0.288 AC: 1002 AN: 3478

EpiCase AF: 0.337

EpiControl AF: 0.333

ClinVar

Significance: Benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 26, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Lys227Lys in exon 8 of POMGNT1: This variant is not expected to have clinical significance because it has been identified in 35% (3000/8600) of European Ameri can chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington. edu/EVS/; dbSNP rs2292487).

Jul 18, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 14, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Autosomal recessive limb-girdle muscular dystrophy type 2O Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Retinitis pigmentosa 76 Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3;C3150417:Autosomal recessive limb-girdle muscular dystrophy type 2O Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3 Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3 Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Retinal dystrophy Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Muscle eye brain disease Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Congenital Muscular Dystrophy, alpha-dystroglycan related Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	8.2
DANN	Benign	0.97
DEOGEN2	Benign	0.0022	T
Eigen	Benign	-0.047
Eigen_PC	Benign	0.020
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.40
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.048
Sift	Uncertain	0.018	D
Sift4G	Benign	0.19	T
Vest4		0.031
ClinPred		0.011	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=85/15	polymorphism (auto)

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: rs2292487; hg19: chr1-46660295; COSMIC: COSV64339346; COSMIC: COSV64339346;