dbSNP rs949335475: GCNT2:p.Lys237AsnfsTer19 (chr6-10557133-A-AT) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001491.3(GCNT2):c.710_711insT(p.Lys237AsnfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000257 in 1,553,960 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GCNT2
NM_001491.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: -0.599

Publications

0 publications found

Variant links:

Genes affected

GCNT2 (HGNC:4204): (glucosaminyl (N-acetyl) transferase 2 (I blood group)) This gene encodes the enzyme responsible for formation of the blood group I antigen. The i and I antigens are distinguished by linear and branched poly-N-acetyllactosaminoglycans, respectively. The encoded protein is the I-branching enzyme, a beta-1,6-N-acetylglucosaminyltransferase responsible for the conversion of fetal i antigen to adult I antigen in erythrocytes during embryonic development. Mutations in this gene have been associated with adult i blood group phenotype. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

GCNT2 Gene-Disease associations (from GenCC):

cataract 13 with adult I phenotype
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
total early-onset cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GCNT2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-10557133-A-AT is Pathogenic according to our data. Variant chr6-10557133-A-AT is described in ClinVar as Pathogenic. ClinVar VariationId is 571381.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001491.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GCNT2	NM_001491.3	MANE Plus Clinical	c.710_711insT	p.Lys237AsnfsTer19	frameshift	Exon 1 of 3	NP_001482.1	Q8N0V5-2
GCNT2	NM_145649.5	MANE Select	c.925+27297_925+27298insT		intron	N/A	NP_663624.1	Q8N0V5-1
GCNT2	NM_001374747.1		c.925+27297_925+27298insT		intron	N/A	NP_001361676.1	Q8N0V5-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GCNT2	ENST00000316170.9	TSL:1 MANE Plus Clinical	c.710_711insT	p.Lys237AsnfsTer19	frameshift	Exon 1 of 3	ENSP00000314844.3	Q8N0V5-2
GCNT2	ENST00000495262.7	TSL:2 MANE Select	c.925+27297_925+27298insT		intron	N/A	ENSP00000419411.2	Q8N0V5-1
GCNT2	ENST00000379597.7	TSL:1	c.925+27297_925+27298insT		intron	N/A	ENSP00000368917.3	Q8N0V5-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000214

AC:

AN:

1401776

Hom.:

Cov.:

AF XY:

0.00000289

AC XY:

AN XY:

692350

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31212

American (AMR)

AF:

0.00

AC:

AN:

33918

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21710

East Asian (EAS)

AF:

0.00

AC:

AN:

39408

South Asian (SAS)

AF:

0.00

AC:

AN:

74098

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50782

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5444

European-Non Finnish (NFE)

AF:

0.00000276

AC:

AN:

1087494

Other (OTH)

AF:

0.00

AC:

AN:

57710

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cataract 13 with adult I phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.60

Mutation Taster

=32/168

disease causing (ClinVar)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over