6-10529216-C-G

Position:

• chr6-10529216-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_145649.5(GCNT2):​c.305C>G​(p.Thr102Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00934 in 1,614,172 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (16 hom., cov: 32)
  • Exomes 𝑓: 0.0095 (103 hom.)
• Consequence: GCNT2 NM_145649.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.63

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067899227).
• BP6: Variant 6-10529216-C-G is Benign according to our data. Variant chr6-10529216-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1182271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00792 (1206/152310) while in subpopulation SAS AF= 0.0176 (85/4828). AF 95% confidence interval is 0.0146. There are 16 homozygotes in gnomad4. There are 597 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 16 BG,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCNT2	NM_145649.5	c.305C>G	p.Thr102Ser	missense_variant	3/5	ENST00000495262.7	NP_663624.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCNT2	ENST00000495262.7	c.305C>G	p.Thr102Ser	missense_variant	3/5	2	NM_145649.5	ENSP00000419411	P3

Frequencies

GnomAD3 genomes AF: 0.00792 AC: 1206 AN: 152192 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.00818

Gnomad ASJ AF: 0.0265

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.00301

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.0138

GnomAD3 exomes AF: 0.00947 AC: 2381 AN: 251454 Hom.: 29 AF XY: 0.0103 AC XY: 1396 AN XY: 135896

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00653

Gnomad ASJ exome AF: 0.0273

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0188

Gnomad FIN exome AF: 0.00319

Gnomad NFE exome AF: 0.00994

Gnomad OTH exome AF: 0.0127

GnomAD4 exome AF: 0.00949 AC: 13867 AN: 1461862 Hom.: 103 Cov.: 33 AF XY: 0.00980 AC XY: 7126 AN XY: 727238

Gnomad4 AFR exome AF: 0.00140

Gnomad4 AMR exome AF: 0.00704

Gnomad4 ASJ exome AF: 0.0280

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0191

Gnomad4 FIN exome AF: 0.00316

Gnomad4 NFE exome AF: 0.00922

Gnomad4 OTH exome AF: 0.0100

GnomAD4 genome AF: 0.00792 AC: 1206 AN: 152310 Hom.: 16 Cov.: 32 AF XY: 0.00802 AC XY: 597 AN XY: 74470

Gnomad4 AFR AF: 0.00202

Gnomad4 AMR AF: 0.00817

Gnomad4 ASJ AF: 0.0265

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0176

Gnomad4 FIN AF: 0.00301

Gnomad4 NFE AF: 0.0106

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.0107 Hom.: 12

Bravo AF: 0.00780

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.0114 AC: 44

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.0115 AC: 99

ExAC AF: 0.00992 AC: 1204

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0125

EpiControl AF: 0.0121

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 09, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

GCNT2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 05, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.049	T;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.79	D
MetaRNN	Benign	0.0068	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Uncertain	-2.4	N;N
REVEL	Benign	0.18
Sift4G	Uncertain	0.018	D;D
Polyphen		0.11	B;B
Vest4		0.50
MutPred		0.72		Loss of methylation at K105 (P = 0.1031);Loss of methylation at K105 (P = 0.1031);
MVP		0.37
MPC		0.046
ClinPred		0.040	T
GERP RS		3.3
Varity_R		0.71
gMVP		0.38

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs77616261; hg19: chr6-10529449;