rs55940927

Positions:

chr6-10626552-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_145649.5(GCNT2):c.1154G>A(p.Arg385His) variant causes a missense change. The variant allele was found at a frequency of 0.0000161 in 1,613,644 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

GCNT2
NM_145649.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 6.37

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-10626552-G-A is Pathogenic according to our data. Variant chr6-10626552-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 9129.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr6-10626552-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCNT2	NM_145649.5 linkuse as main transcript	c.1154G>A	p.Arg385His	missense_variant	5/5	ENST00000495262.7	NP_663624.1
GCNT2	NM_001491.3 linkuse as main transcript	c.1148G>A	p.Arg383His	missense_variant	3/3	ENST00000316170.9	NP_001482.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCNT2	ENST00000495262.7 linkuse as main transcript	c.1154G>A	p.Arg385His	missense_variant	5/5	2	NM_145649.5	ENSP00000419411	P3	Q8N0V5-1
GCNT2	ENST00000316170.9 linkuse as main transcript	c.1148G>A	p.Arg383His	missense_variant	3/3	1	NM_001491.3	ENSP00000314844		Q8N0V5-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000636

AC:

AN:

251388

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000489

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461492

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727074

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000810

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cataract 13 with adult I phenotype

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2021	ClinVar contains an entry for this variant (Variation ID: 9129). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg383 amino acid residue in GCNT2. Other variant(s) that disrupt this residue have been observed in individuals with GCNT2-related conditions (PMID: 29770612, 29914532), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects GCNT2 function (PMID: 11739194, 12468428). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant is also known as c.1154G_x0008_>A (p.Arg385His). This missense change has been observed in individuals with congenital cataract with adult i phenotype (PMID: 29914532). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs55940927, gnomAD 0.06%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 383 of the GCNT2 protein (p.Arg383His). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 15, 2001	- -
Uncertain significance, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest no damaging effect of the variant on gene or gene product (REVEL: 0.25; 3Cnet: 0.04). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GCNT2 related disorder (ClinVar ID: VCV000009129 / PMID: 29914532). A different missense change at the same codon (p.Arg385Cys) has been reported to be associated with GCNT2 related disorder (PMID: 29770612). However the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significanceaccording to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;T;T;.;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.81

.;.;.;.;T

M_CAP

Benign

0.031

MetaRNN

Uncertain

0.45

T;T;T;T;T

MetaSVM

Benign

-0.49

MutationAssessor

Pathogenic

3.4

.;M;M;.;M

MutationTaster

Benign

1.0

A;A;A;A;A

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.7

D;D;D;D;D

REVEL

Benign

0.25

Sift

Uncertain

0.0060

D;.;.;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;B;B;.;.

Vest4

0.66

MVP

0.67

MPC

0.016

ClinPred

0.50

GERP RS

3.7

Varity_R

0.59

gMVP

0.50

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over