5-149981658-A-T

Variant names:

• chr5-149981658-A-T
• rs3776070
• NM_000112.4:c.2065A>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000112.4(SLC26A2):​c.2065A>T​(p.Thr689Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,613,420 control chromosomes in the GnomAD database, including 20,943 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T689A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.19 (3314 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17629 hom.)
• Consequence: SLC26A2 NM_000112.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18 O:1
• Conservation: PhyloP100: 2.47
• Publications: 31 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: Benign. The variant received -17 ACMG points.

• PM1: In a domain STAS (size 151) in uniprot entity S26A2_HUMAN there are 11 pathogenic changes around while only 3 benign (79%) in NM_000112.4
• 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 multiple epiphyseal dysplasia type 4, atelosteogenesis type II, achondrogenesis type IB, diastrophic dysplasia, multiple epiphyseal dysplasia.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0040397644).
• BP6: Variant 5-149981658-A-T is Benign according to our data. Variant chr5-149981658-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 65560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

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.2065A>T	p.Thr689Ser	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.2065A>T	p.Thr689Ser	missense	Exon 3 of 3	ENSP00000286298.4	P50443
	SLC26A2	ENST00000862081.1		c.2065A>T	p.Thr689Ser	missense	Exon 4 of 4	ENSP00000532140.1
	SLC26A2	ENST00000862082.1		c.2065A>T	p.Thr689Ser	missense	Exon 3 of 3	ENSP00000532141.1

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29501 AN: 151990 Hom.: 3298 Cov.: 32

Gnomad AFR AF: 0.290

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.188

GnomAD2 exomes AF: 0.172 AC: 43176 AN: 250630 AF XY: 0.162

Gnomad AFR exome AF: 0.295

Gnomad AMR exome AF: 0.341

Gnomad ASJ exome AF: 0.158

Gnomad EAS exome AF: 0.101

Gnomad FIN exome AF: 0.143

Gnomad NFE exome AF: 0.139

Gnomad OTH exome AF: 0.167

GnomAD4 exome AF: 0.148 AC: 215700 AN: 1461312 Hom.: 17629 Cov.: 34 AF XY: 0.145 AC XY: 105463 AN XY: 726960

African (AFR) AF: 0.293 AC: 9789 AN: 33466

American (AMR) AF: 0.332 AC: 14828 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 4060 AN: 26122

East Asian (EAS) AF: 0.0900 AC: 3571 AN: 39694

South Asian (SAS) AF: 0.107 AC: 9202 AN: 86170

European-Finnish (FIN) AF: 0.147 AC: 7818 AN: 53344

Middle Eastern (MID) AF: 0.198 AC: 1143 AN: 5768

European-Non Finnish (NFE) AF: 0.140 AC: 155631 AN: 1111698

Other (OTH) AF: 0.160 AC: 9658 AN: 60378

GnomAD4 genome AF: 0.194 AC: 29558 AN: 152108 Hom.: 3314 Cov.: 32 AF XY: 0.195 AC XY: 14516 AN XY: 74374

African (AFR) AF: 0.290 AC: 12039 AN: 41482

American (AMR) AF: 0.289 AC: 4408 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 515 AN: 3466

East Asian (EAS) AF: 0.103 AC: 534 AN: 5170

South Asian (SAS) AF: 0.101 AC: 488 AN: 4820

European-Finnish (FIN) AF: 0.135 AC: 1426 AN: 10600

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.141 AC: 9584 AN: 67976

Other (OTH) AF: 0.186 AC: 393 AN: 2114

Alfa AF: 0.137 Hom.: 1168

Bravo AF: 0.211

TwinsUK AF: 0.138 AC: 513

ALSPAC AF: 0.130 AC: 500

ESP6500AA AF: 0.288 AC: 1270

ESP6500EA AF: 0.145 AC: 1251

ExAC AF: 0.166 AC: 20109

Asia WGS AF: 0.138 AC: 482 AN: 3478

EpiCase AF: 0.146

EpiControl AF: 0.148

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	13
DANN	Benign	0.19
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-2.2	N
PhyloP100		2.5
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	1.4	N
REVEL	Uncertain	0.31
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.018
MutPred		0.74		Gain of disorder (P = 0.0916)
MPC		0.044
ClinPred		0.0057	T
GERP RS		5.7
Varity_R		0.13
gMVP		0.22
Mutation Taster		=98/2	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: rs3776070; hg19: chr5-149361221; COSMIC: COSV53824588; COSMIC: COSV53824588;