NM_021615.5:c.521A>G

Variant names:

• chr16-75479308-T-C
• rs28937877
• NM_021615.5:c.521A>G

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_021615.5(CHST6):​c.521A>G​(p.Lys174Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV000398964: Functional studies in HeLa cells demonstrated that the p.Lys174Arg variant resulted in a loss of enzyme activity and a failure of the CHST6 protein to produce highly sulphated keratin sulfate, which would result in the accumulation of non-sulfated keratin sulfate within the keratocytes and corneal epithelium, which is characteristic of macular corneal dystrophy (Akama et al. 2001).". Synonymous variant affecting the same amino acid position (i.e. K174K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CHST6 NM_021615.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.91
• Publications: 8 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 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000398964: Functional studies in HeLa cells demonstrated that the p.Lys174Arg variant resulted in a loss of enzyme activity and a failure of the CHST6 protein to produce highly sulphated keratin sulfate, which would result in the accumulation of non-sulfated keratin sulfate within the keratocytes and corneal epithelium, which is characteristic of macular corneal dystrophy (Akama et al. 2001).
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_021615.5
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.989
• PP5: Variant 16-75479308-T-C is Pathogenic according to our data. Variant chr16-75479308-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 5071.Status of the report is criteria_provided_single_submitter, 1 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.521A>G	p.Lys174Arg	missense	Exon 3 of 3	NP_067628.1	Q9GZX3
	CHST6	NR_163480.1		n.733+2509A>G		intron	N/A
	CHST6	NR_163481.1		n.577+2509A>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.521A>G	p.Lys174Arg	missense	Exon 3 of 3	ENSP00000328983.4	Q9GZX3
	CHST6	ENST00000390664.3	TSL:1	c.521A>G	p.Lys174Arg	missense	Exon 4 of 4	ENSP00000375079.2	Q9GZX3
	CHST6	ENST00000970639.1		c.521A>G	p.Lys174Arg	missense	Exon 3 of 3	ENSP00000640698.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460970 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726840

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52812

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111780

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Macular corneal dystrophy (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.90		Loss of ubiquitination at K174 (P = 0.0309)
MVP		0.99
MPC		0.87
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.96
gMVP		0.99
Mutation Taster		=8/92	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: rs28937877; hg19: chr16-75513206;