rs2230291

Variant names:

• chr12-64747808-C-T
• rs2230291
• NM_002076.4:c.363G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-64747808-C-T
• chr12-64747808-C-A
• chr12-64747808-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002076.4(GNS):​c.363G>A​(p.Lys121Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,608,308 control chromosomes in the GnomAD database, including 11,810 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.089 (813 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10997 hom.)
• Consequence: GNS NM_002076.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.135
• Publications: 8 publications found

Genes affected

GNS (HGNC:4422): (glucosamine (N-acetyl)-6-sulfatase) The product of this gene is a lysosomal enzyme found in all cells. It is involved in the catabolism of heparin, heparan sulphate, and keratan sulphate. Deficiency of this enzyme results in the accumulation of undegraded substrate and the lysosomal storage disorder mucopolysaccharidosis type IIID (Sanfilippo D syndrome). Mucopolysaccharidosis type IIID is the least common of the four subtypes of Sanfilippo syndrome. [provided by RefSeq, Jul 2008]

GNS Gene-Disease associations (from GenCC):

• mucopolysaccharidosis type 3D

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 12-64747808-C-T is Benign according to our data. Variant chr12-64747808-C-T is described in ClinVar as Benign. ClinVar VariationId is 94030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.135 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002076.4. 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
	GNS	NM_002076.4	MANE Select	c.363G>A	p.Lys121Lys	synonymous	Exon 3 of 14	NP_002067.1	P15586-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNS	ENST00000258145.8	TSL:1 MANE Select	c.363G>A	p.Lys121Lys	synonymous	Exon 3 of 14	ENSP00000258145.3	P15586-1
	GNS	ENST00000418919.6	TSL:1	c.195G>A	p.Lys65Lys	synonymous	Exon 2 of 13	ENSP00000413130.2	H7C3P4
	GNS	ENST00000967913.1		c.477G>A	p.Lys159Lys	synonymous	Exon 3 of 14	ENSP00000637972.1

Frequencies

GnomAD3 genomes AF: 0.0888 AC: 13512 AN: 152098 Hom.: 814 Cov.: 32

Gnomad AFR AF: 0.0221

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.0785

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0213

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.0937

GnomAD2 exomes AF: 0.0924 AC: 23248 AN: 251476 AF XY: 0.0929

Gnomad AFR exome AF: 0.0201

Gnomad AMR exome AF: 0.0612

Gnomad ASJ exome AF: 0.163

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.141

Gnomad NFE exome AF: 0.128

Gnomad OTH exome AF: 0.115

GnomAD4 exome AF: 0.115 AC: 168050 AN: 1456092 Hom.: 10997 Cov.: 29 AF XY: 0.113 AC XY: 82068 AN XY: 724802

African (AFR) AF: 0.0192 AC: 641 AN: 33386

American (AMR) AF: 0.0660 AC: 2951 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 3988 AN: 26084

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39678

South Asian (SAS) AF: 0.0289 AC: 2493 AN: 86152

European-Finnish (FIN) AF: 0.140 AC: 7474 AN: 53418

Middle Eastern (MID) AF: 0.110 AC: 633 AN: 5746

European-Non Finnish (NFE) AF: 0.130 AC: 143392 AN: 1106698

Other (OTH) AF: 0.107 AC: 6471 AN: 60214

GnomAD4 genome AF: 0.0888 AC: 13514 AN: 152216 Hom.: 813 Cov.: 32 AF XY: 0.0882 AC XY: 6566 AN XY: 74432

African (AFR) AF: 0.0221 AC: 917 AN: 41540

American (AMR) AF: 0.0784 AC: 1199 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 572 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.0219 AC: 106 AN: 4830

European-Finnish (FIN) AF: 0.151 AC: 1597 AN: 10580

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.129 AC: 8804 AN: 67996

Other (OTH) AF: 0.0922 AC: 195 AN: 2114

Alfa AF: 0.106 Hom.: 636

Bravo AF: 0.0826

Asia WGS AF: 0.0190 AC: 67 AN: 3478

EpiCase AF: 0.135

EpiControl AF: 0.134

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Mucopolysaccharidosis, MPS-III-D (4)
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Sanfilippo syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.84
DANN	Benign	0.43
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism (auto)

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: rs2230291; hg19: chr12-65141588;