rs104893919

Variant names:

• chr5-149978184-C-T
• rs104893919
• NM_000112.4:c.532C>T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_000112.4(SLC26A2):​c.532C>T​(p.Arg178*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000967 in 1,612,622 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: "SCV002061200: "Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID:11448940" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R178R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000095 (0 hom.)
• Consequence: SLC26A2 NM_000112.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:24 O:1
• Conservation: PhyloP100: 1.35
• Publications: 21 publications found

Genes affected

SLC26A2 (HGNC:10994): (solute carrier family 26 member 2) The diastrophic dysplasia sulfate transporter is a transmembrane glycoprotein implicated in the pathogenesis of several human chondrodysplasias. It apparently is critical in cartilage for sulfation of proteoglycans and matrix organization. [provided by RefSeq, Jul 2008]

SLC26A2 Gene-Disease associations (from GenCC):

• achondrogenesis type IB

  Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: ClinGen, G2P, Ambry Genetics, Orphanet
• atelosteogenesis type II

  Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Orphanet
• diastrophic dysplasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• multiple epiphyseal dysplasia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• multiple epiphyseal dysplasia type 4

  Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P
• SLC26A2-related skeletal dysplasia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• skeletal dysplasia

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV002061200: "Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 11448940; 15294877) - PS3_moderate."; SCV000695419: This variant has been reported in multiple STRO patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. **Karniski_2004**; SCV000916095: "In Xenopus oocytes, the p.Arg178Ter variant was shown to have significantly reduced (<10%) sulfate transport compared to wildtype, and similar findings were noted in HEK-293 cells." (Karniski et al. 2001; Karniski et al. 2004); SCV005361527: Functional studies support the pathogenicity of this change (Karniski. 2001. PubMed ID: 11448940).
• PP5: Variant 5-149978184-C-T is Pathogenic according to our data. Variant chr5-149978184-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 4092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000112.4. 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
	SLC26A2	NM_000112.4	MANE Select	c.532C>T	p.Arg178*	stop_gained	Exon 2 of 3	NP_000103.2	P50443

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A2	ENST00000286298.5	TSL:1 MANE Select	c.532C>T	p.Arg178*	stop_gained	Exon 2 of 3	ENSP00000286298.4	P50443
	SLC26A2	ENST00000862081.1		c.532C>T	p.Arg178*	stop_gained	Exon 3 of 4	ENSP00000532140.1
	SLC26A2	ENST00000862082.1		c.532C>T	p.Arg178*	stop_gained	Exon 2 of 3	ENSP00000532141.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152040 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000131 AC: 33 AN: 251008 AF XY: 0.000133

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000952 AC: 139 AN: 1460582 Hom.: 0 Cov.: 33 AF XY: 0.0000950 AC XY: 69 AN XY: 726340

African (AFR) AF: 0.0000598 AC: 2 AN: 33470

American (AMR) AF: 0.000268 AC: 12 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.000103 AC: 114 AN: 1110896

Other (OTH) AF: 0.000133 AC: 8 AN: 60346

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152040 Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7 AN XY: 74260

African (AFR) AF: 0.0000483 AC: 2 AN: 41374

American (AMR) AF: 0.000197 AC: 3 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000124 Hom.: 0

Bravo AF: 0.000132

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	not provided (7)
5	-	-	Achondrogenesis, type IB (5)
3	-	-	Atelosteogenesis type II (3)
2	-	-	Diastrophic dysplasia (3)
2	-	-	Diastrophic dysplasia;C0265274:Achondrogenesis, type IB;C1847593:Multiple epiphyseal dysplasia type 4;C1850554:Atelosteogenesis type II (2)
2	-	-	SLC26A2-related disorder (2)
1	-	-	3MC syndrome 2 (1)
1	-	-	Multiple epiphyseal dysplasia type 4 (1)
1	-	-	Sulfate transporter-related osteochondrodysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		1.4
Vest4		0.86
GERP RS		5.4
PromoterAI		-0.030	Neutral
Mutation Taster		=8/192	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: rs104893919; hg19: chr5-149357747; COSMIC: COSV105841713; COSMIC: COSV105841713;