6-10529416-G-A

Variant names:

• chr6-10529416-G-A
• rs137853339
• NM_145649.5:c.505G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_145649.5(GCNT2):​c.505G>A​(p.Ala169Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GCNT2 NM_145649.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.67
• Publications: 7 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.763
• PP5: Variant 6-10529416-G-A is Pathogenic according to our data. Variant chr6-10529416-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 9131.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145649.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCNT2	NM_145649.5	MANE Select	c.505G>A	p.Ala169Thr	missense	Exon 3 of 5	NP_663624.1	Q8N0V5-1
	GCNT2	NM_001374747.1		c.505G>A	p.Ala169Thr	missense	Exon 1 of 3	NP_001361676.1	Q8N0V5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCNT2	ENST00000495262.7	TSL:2 MANE Select	c.505G>A	p.Ala169Thr	missense	Exon 3 of 5	ENSP00000419411.2	Q8N0V5-1
	GCNT2	ENST00000379597.7	TSL:1	c.505G>A	p.Ala169Thr	missense	Exon 1 of 3	ENSP00000368917.3	Q8N0V5-1
	GCNT2	ENST00000410107.5	TSL:1	c.67+20258G>A		intron	N/A	ENSP00000386321.1	B7ZBL3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	ADULT i BLOOD GROUP PHENOTYPE (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.87	T
MutationAssessor	Pathogenic	4.0	H
PhyloP100		6.7
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.47
Sift4G	Pathogenic	0.0	D
Polyphen		0.96	D
Vest4		0.48
MutPred		0.86		Gain of phosphorylation at A169 (P = 0.0809)
MVP		0.62
MPC		0.096
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.94
gMVP		0.49
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs137853339; hg19: chr6-10529649;