Genetic Variant CHST6:p.Arg162Gly (chr16-75479345-G-C) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBA1

The NM_021615.5(CHST6):c.484C>G(p.Arg162Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0495 in 1,612,722 control chromosomes in the GnomAD database, including 2,321 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R162Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.035 ( 137 hom., cov: 33)

Exomes 𝑓: 0.051 ( 2184 hom. )

Consequence

CHST6
NM_021615.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.41

Publications

16 publications found

Variant links:

Genes affected

CHST6 (HGNC:6938): (carbohydrate sulfotransferase 6) The protein encoded by this gene is an enzyme that catalyzes the transfer of a sulfate group to the GlcNAc residues of keratan. Keratan sulfate helps maintain corneal transparency. Defects in this gene are a cause of macular corneal dystrophy (MCD). [provided by RefSeq, Jan 2010]

CHST6 Gene-Disease associations (from GenCC):

macular corneal dystrophy
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet

CHST6 links:

ENSG00000203472 (HGNC:):

ENSG00000203472 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_021615.5

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: -0.89985 (below the threshold of 3.09). Trascript score misZ: -1.6448 (below the threshold of 3.09). GenCC associations: The gene is linked to macular corneal dystrophy.

BP4

Computational evidence support a benign effect (MetaRNN=0.0051915944).

BP6

Variant 16-75479345-G-C is Benign according to our data. Variant chr16-75479345-G-C is described in ClinVar as Benign. ClinVar VariationId is 320611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0554 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021615.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHST6	NM_021615.5	MANE Select	c.484C>G	p.Arg162Gly	missense	Exon 3 of 3	NP_067628.1	Q9GZX3
CHST6	NR_163480.1		n.733+2472C>G		intron	N/A
CHST6	NR_163481.1		n.577+2472C>G		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHST6	ENST00000332272.9	TSL:3 MANE Select	c.484C>G	p.Arg162Gly	missense	Exon 3 of 3	ENSP00000328983.4	Q9GZX3
CHST6	ENST00000390664.3	TSL:1	c.484C>G	p.Arg162Gly	missense	Exon 4 of 4	ENSP00000375079.2	Q9GZX3
CHST6	ENST00000970639.1		c.484C>G	p.Arg162Gly	missense	Exon 3 of 3	ENSP00000640698.1

Frequencies

GnomAD3 genomes

AF:

0.0355

AC:

5396

AN:

152214

Hom.:

137

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0112

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.0307

Gnomad ASJ

AF:

0.0551

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00496

Gnomad FIN

AF:

0.0257

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0568

Gnomad OTH

AF:

0.0382

GnomAD2 exomes

AF:

0.0352

AC:

8681

AN:

246334

AF XY:

0.0349

show subpopulations

Gnomad AFR exome

AF:

0.0108

Gnomad AMR exome

AF:

0.0211

Gnomad ASJ exome

AF:

0.0533

Gnomad EAS exome

AF:

0.0000555

Gnomad FIN exome

AF:

0.0291

Gnomad NFE exome

AF:

0.0559

Gnomad OTH exome

AF:

0.0447

GnomAD4 exome

AF:

0.0509

AC:

74388

AN:

1460390

Hom.:

2184

Cov.:

AF XY:

0.0496

AC XY:

36028

AN XY:

726556

show subpopulations

African (AFR)

AF:

0.00876

AC:

293

AN:

33462

American (AMR)

AF:

0.0241

AC:

1077

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0532

AC:

1389

AN:

26114

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39690

South Asian (SAS)

AF:

0.00671

AC:

579

AN:

86248

European-Finnish (FIN)

AF:

0.0340

AC:

1776

AN:

52288

Middle Eastern (MID)

AF:

0.0284

AC:

164

AN:

5768

European-Non Finnish (NFE)

AF:

0.0595

AC:

66140

AN:

1111744

Other (OTH)

AF:

0.0492

AC:

2969

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

5629

11258

16886

22515

28144

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2390

4780

7170

9560

11950

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0354

AC:

5397

AN:

152332

Hom.:

137

Cov.:

AF XY:

0.0322

AC XY:

2400

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0111

AC:

463

AN:

41584

American (AMR)

AF:

0.0307

AC:

470

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0551

AC:

191

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00497

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0257

AC:

273

AN:

10622

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0569

AC:

3867

AN:

68016

Other (OTH)

AF:

0.0378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

266

532

798

1064

1330

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0381

Hom.:

Bravo

AF:

0.0367

TwinsUK

AF:

0.0585

AC:

217

ALSPAC

AF:

0.0638

AC:

246

ESP6500AA

AF:

0.0109

AC:

ESP6500EA

AF:

0.0529

AC:

454

ExAC

AF:

0.0350

AC:

4243

EpiCase

AF:

0.0595

EpiControl

AF:

0.0607

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Macular corneal dystrophy (2)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.59

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.28

MetaRNN

Benign

0.0052

MetaSVM

Uncertain

0.42

MutationAssessor

Benign

0.34

PhyloP100

2.4

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.34

Sift

Uncertain

0.018

Sift4G

Uncertain

0.044

Polyphen

0.0

Vest4

0.015

MPC

0.41

ClinPred

0.013

GERP RS

2.5

Varity_R

0.12

gMVP

0.92

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over