Genetic Variant CHST6:p.Gln331His (chr16-75478836-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_021615.5(CHST6):c.993G>T(p.Gln331His) variant causes a missense change. The variant allele was found at a frequency of 0.00232 in 1,613,470 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q331R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0016 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0024 ( 63 hom. )

Consequence

CHST6
NM_021615.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 4.82

Publications

12 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)

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 -12 ACMG points.

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=0.011656791).

BP6

Variant 16-75478836-C-A is Benign according to our data. Variant chr16-75478836-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 196507.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00163 (249/152370) while in subpopulation SAS AF = 0.0213 (103/4828). AF 95% confidence interval is 0.018. There are 2 homozygotes in GnomAd4. There are 149 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

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
CHST6	NM_021615.5	MANE Select	c.993G>T	p.Gln331His	missense	Exon 3 of 3	NP_067628.1
CHST6	NR_163480.1		n.733+2981G>T		intron	N/A
CHST6	NR_163481.1		n.577+2981G>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CHST6	ENST00000332272.9	TSL:3 MANE Select	c.993G>T	p.Gln331His	missense	Exon 3 of 3	ENSP00000328983.4
CHST6	ENST00000390664.3	TSL:1	c.993G>T	p.Gln331His	missense	Exon 4 of 4	ENSP00000375079.2
CHST6	ENST00000970639.1		c.993G>T	p.Gln331His	missense	Exon 3 of 3	ENSP00000640698.1

Frequencies

GnomAD3 genomes

AF:

0.00162

AC:

246

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00307

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000838

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00404

AC:

1014

AN:

250718

AF XY:

0.00530

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.000752

Gnomad ASJ exome

AF:

0.0104

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000857

Gnomad OTH exome

AF:

0.00245

GnomAD4 exome

AF:

0.00239

AC:

3495

AN:

1461100

Hom.:

Cov.:

AF XY:

0.00322

AC XY:

2344

AN XY:

726886

show subpopulations

African (AFR)

AF:

0.000388

AC:

AN:

33476

American (AMR)

AF:

0.000648

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0103

AC:

268

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0261

AC:

2254

AN:

86258

European-Finnish (FIN)

AF:

0.0000759

AC:

AN:

52730

Middle Eastern (MID)

AF:

0.00572

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000669

AC:

744

AN:

1111942

Other (OTH)

AF:

0.00248

AC:

150

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

324

649

973

1298

1622

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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:

0.00163

AC:

249

AN:

152370

Hom.:

Cov.:

AF XY:

0.00200

AC XY:

149

AN XY:

74514

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41586

American (AMR)

AF:

0.00307

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00778

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.0213

AC:

103

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000838

AC:

AN:

68032

Other (OTH)

AF:

0.00284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00145

Hom.:

Bravo

AF:

0.00108

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.00414

AC:

503

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.00147

EpiControl

AF:

0.00136

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Macular corneal dystrophy (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.012

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.3

PhyloP100

4.8

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.62

Sift

Uncertain

0.0020

Sift4G

Benign

0.087

Polyphen

1.0

Vest4

0.51

MutPred

0.48

Loss of helix (P = 0.0072)

MVP

1.0

MPC

0.88

ClinPred

0.027

GERP RS

4.9

Varity_R

0.63

gMVP

0.67

Mutation Taster

=92/8

polymorphism

(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