rs1554129925

Variant names:

• chr6-10557000-T-G
• rs1554129925
• NM_001491.3:c.577T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001491.3(GCNT2):​c.577T>G​(p.Phe193Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GCNT2 NM_001491.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.08

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCNT2	NM_001491.3	c.577T>G	p.Phe193Val	missense_variant	Exon 1 of 3	ENST00000316170.9	NP_001482.1
GCNT2	NM_145649.5	c.925+27164T>G		intron_variant	Intron 3 of 4	ENST00000495262.7	NP_663624.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCNT2	ENST00000316170.9	c.577T>G	p.Phe193Val	missense_variant	Exon 1 of 3	1	NM_001491.3	ENSP00000314844.3
GCNT2	ENST00000495262.7	c.925+27164T>G		intron_variant	Intron 3 of 4	2	NM_145649.5	ENSP00000419411.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250756 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135498

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461472 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727044

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cataract 13 with adult I phenotype Uncertain:1

Feb 25, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a GCNT2-related disease. This sequence change replaces phenylalanine with valine at codon 193 of the GCNT2 protein (p.Phe193Val). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	20
DANN	Uncertain	0.99
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-0.95	T
PROVEAN	Pathogenic	-6.9	D;.
REVEL	Uncertain	0.52
Sift4G	Pathogenic	0.0010	D;.
Vest4		0.79
MutPred		0.93		Loss of ubiquitination at K196 (P = 0.0877);Loss of ubiquitination at K196 (P = 0.0877);
MVP		0.60
ClinPred		0.99	D
GERP RS		5.0

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554129925; hg19: chr6-10557233;