rs55940927

chr6-10626552-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

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). Synonymous variant affecting the same amino acid position (i.e. R385R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: GCNT2 NM_145649.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 6.37

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 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	UniProt
GCNT2	NM_145649.5	c.1154G>A	p.Arg385His	missense_variant	5/5	ENST00000495262.7
GCNT2	NM_001491.3	c.1148G>A	p.Arg383His	missense_variant	3/3	ENST00000316170.9

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152152 Hom.: 0 Cov.: 32

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: 16 AN: 251388 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135864

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: 23 AN: 1461492 Hom.: 0 Cov.: 30 AF XY: 0.0000165 AC XY: 12 AN XY: 727074

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: 3 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74340

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: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cataract 13 with adult I phenotype Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	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	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Pathogenic	26
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	D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.45	T;T;T;T;T
MetaSVM	Benign	-0.49	T
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.55	T
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	D
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

Other links and lift over

dbSNP: rs55940927; hg19: chr6-10626785;