rs1554129925

chr6-10557000-T-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/exons	MANE	UniProt
GCNT2	NM_001491.3	c.577T>G	p.Phe193Val	missense_variant	1/3	ENST00000316170.9
GCNT2	NM_145649.5	c.925+27164T>G		intron_variant		ENST00000495262.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCNT2	ENST00000316170.9	c.577T>G	p.Phe193Val	missense_variant	1/3	1	NM_001491.3
GCNT2	ENST00000495262.7	c.925+27164T>G		intron_variant		2	NM_145649.5	P3

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 25, 2017

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. 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. 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"). 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. -

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
MutationTaster	Benign	1.0	D;D;D;D
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;