rs28937879

Variant names:

• chr16-75479230-A-C
• rs28937879
• NM_021615.5:c.599T>G

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PP2 PP3_Strong PP5_Very_Strong

The NM_021615.5(CHST6):​c.599T>G​(p.Leu200Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000306 in 1,611,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000966880: "This variant has been identified in 0.03% (30/115,942) of chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: CHST6 NM_021615.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 9.15
• Publications: 15 publications found

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

ENSG00000203472 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000966880: "This variant has been identified in 0.03% (30/115,942) of chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs28937879). Although it has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In summary, this variant meets our criteria to be classified as pathogenic for macular corneal dystrophy in an autosomal recessive manner based upon its biallelic occurrence in affected individuals and functional evidence." Based on the instructions, the correct output should be a quoted snippet containing the relevant evidence. However, the provided text does not directly state what the functional evidence is. Given the instruction to be eager when a reference is provided, the closest match to the evidence would be the summary statement which includes "functional evidence". Therefore, the most appropriate response based on the given format and instructions would be: "In summary, this variant meets our criteria to be classified as pathogenic for macular corneal dystrophy in an autosomal recessive manner based upon its biallelic occurrence in affected individuals and functional evidence." However, since the exact functional study details are not explicitly stated, the more accurate response according to the strict interpretation of the instructions would be: `no`
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941
• PP5: Variant 16-75479230-A-C is Pathogenic according to our data. Variant chr16-75479230-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 5075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHST6	NM_021615.5	MANE Select	c.599T>G	p.Leu200Arg	missense	Exon 3 of 3	NP_067628.1	Q9GZX3
	CHST6	NR_163480.1		n.733+2587T>G		intron	N/A
	CHST6	NR_163481.1		n.577+2587T>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHST6	ENST00000332272.9	TSL:3 MANE Select	c.599T>G	p.Leu200Arg	missense	Exon 3 of 3	ENSP00000328983.4	Q9GZX3
	CHST6	ENST00000390664.3	TSL:1	c.599T>G	p.Leu200Arg	missense	Exon 4 of 4	ENSP00000375079.2	Q9GZX3
	CHST6	ENST00000970639.1		c.599T>G	p.Leu200Arg	missense	Exon 3 of 3	ENSP00000640698.1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000225 AC: 55 AN: 244732 AF XY: 0.000225

Gnomad AFR exome AF: 0.0000635

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000495

Gnomad NFE exome AF: 0.000455

Gnomad OTH exome AF: 0.000333

GnomAD4 exome AF: 0.000316 AC: 461 AN: 1459028 Hom.: 0 Cov.: 31 AF XY: 0.000314 AC XY: 228 AN XY: 725996

African (AFR) AF: 0.000120 AC: 4 AN: 33460

American (AMR) AF: 0.0000224 AC: 1 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.0000587 AC: 3 AN: 51112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000399 AC: 443 AN: 1111644

Other (OTH) AF: 0.000166 AC: 10 AN: 60334

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152192 Hom.: 0 Cov.: 33 AF XY: 0.000202 AC XY: 15 AN XY: 74366

African (AFR) AF: 0.0000723 AC: 3 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000189 Hom.: 0

Bravo AF: 0.000185

ExAC AF: 0.000248 AC: 30

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Macular corneal dystrophy (8)
1	-	-	CHST6-related disorder (1)
1	-	-	Macular corneal dystrophy, type II (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		9.1
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MVP		0.91
MPC		1.3
ClinPred		0.64	D
GERP RS		4.7
Varity_R		0.99
gMVP		0.96
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs28937879; hg19: chr16-75513128;