rs78676079

Variant names:

• chr5-149981067-C-T
• rs78676079
• NM_000112.4:c.1474C>T
• SLC26A2 p.Arg492Trp

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000112.4(SLC26A2):​c.1474C>T​(p.Arg492Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0207 in 1,614,088 control chromosomes in the GnomAD database, including 428 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R492R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.016 (26 hom., cov: 32)
  • Exomes 𝑓: 0.021 (402 hom.)
• Consequence: SLC26A2 NM_000112.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19 O:1
• Conservation: PhyloP100: 1.51
• Publications: 16 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: Orphanet, ClinGen, G2P, Ambry Genetics
• atelosteogenesis type II

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

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

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

  Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics
• 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: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 26 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 0.031413 (below the threshold of 3.09). Trascript score misZ: 1.4892 (below the threshold of 3.09). GenCC associations: The gene is linked to achondrogenesis type IB, multiple epiphyseal dysplasia, atelosteogenesis type II, diastrophic dysplasia, multiple epiphyseal dysplasia type 4, SLC26A2-related skeletal dysplasia, skeletal dysplasia.
• BP4: Computational evidence support a benign effect (MetaRNN=0.01479131).
• BP6: Variant 5-149981067-C-T is Benign according to our data. Variant chr5-149981067-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 65559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0158 (2405/152270) while in subpopulation NFE AF = 0.025 (1701/68014). AF 95% confidence interval is 0.024. There are 26 homozygotes in GnomAd4. There are 1134 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

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.1474C>T	p.Arg492Trp	missense	Exon 3 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.1474C>T	p.Arg492Trp	missense	Exon 3 of 3	ENSP00000286298.4	P50443
	SLC26A2	ENST00000862081.1		c.1474C>T	p.Arg492Trp	missense	Exon 4 of 4	ENSP00000532140.1
	SLC26A2	ENST00000862082.1		c.1474C>T	p.Arg492Trp	missense	Exon 3 of 3	ENSP00000532141.1

Frequencies

GnomAD3 genomes AF: 0.0158 AC: 2405 AN: 152152 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.00391

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.000961

Gnomad SAS AF: 0.00664

Gnomad FIN AF: 0.0199

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.0250

Gnomad OTH AF: 0.0173

GnomAD2 exomes AF: 0.0167 AC: 4201 AN: 251248 AF XY: 0.0168

Gnomad AFR exome AF: 0.00344

Gnomad AMR exome AF: 0.0104

Gnomad ASJ exome AF: 0.0214

Gnomad EAS exome AF: 0.000979

Gnomad FIN exome AF: 0.0201

Gnomad NFE exome AF: 0.0246

Gnomad OTH exome AF: 0.0186

GnomAD4 exome AF: 0.0212 AC: 31038 AN: 1461818 Hom.: 402 Cov.: 34 AF XY: 0.0211 AC XY: 15365 AN XY: 727210

African (AFR) AF: 0.00385 AC: 129 AN: 33478

American (AMR) AF: 0.0102 AC: 454 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 588 AN: 26134

East Asian (EAS) AF: 0.000605 AC: 24 AN: 39698

South Asian (SAS) AF: 0.00766 AC: 661 AN: 86254

European-Finnish (FIN) AF: 0.0209 AC: 1116 AN: 53420

Middle Eastern (MID) AF: 0.0210 AC: 121 AN: 5768

European-Non Finnish (NFE) AF: 0.0241 AC: 26841 AN: 1111950

Other (OTH) AF: 0.0183 AC: 1104 AN: 60394

GnomAD4 genome AF: 0.0158 AC: 2405 AN: 152270 Hom.: 26 Cov.: 32 AF XY: 0.0152 AC XY: 1134 AN XY: 74458

African (AFR) AF: 0.00390 AC: 162 AN: 41568

American (AMR) AF: 0.0103 AC: 157 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0228 AC: 79 AN: 3472

East Asian (EAS) AF: 0.000963 AC: 5 AN: 5190

South Asian (SAS) AF: 0.00664 AC: 32 AN: 4818

European-Finnish (FIN) AF: 0.0199 AC: 211 AN: 10608

Middle Eastern (MID) AF: 0.0274 AC: 8 AN: 292

European-Non Finnish (NFE) AF: 0.0250 AC: 1701 AN: 68014

Other (OTH) AF: 0.0171 AC: 36 AN: 2108

Alfa AF: 0.0213 Hom.: 142

Bravo AF: 0.0141

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.0241

EpiControl AF: 0.0216

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	0.46	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.5
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.80
gMVP		0.85
Mutation Taster		=78/22	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs78676079; hg19: chr5-149360630; COSMIC: COSV53825620; COSMIC: COSV53825620;