5-149980750-C-T

Variant names:

• chr5-149980750-C-T
• rs386833493
• NM_000112.4:c.1157C>T
• SLC26A2 p.Ala386Val

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000112.4(SLC26A2):​c.1157C>T​(p.Ala386Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005911657: Experimental studies confirmed its pathogenic effect on the protein. It reduced the transportation of sulfates and oxalates, and also reduced the surface abundance of the protein." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A386E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC26A2 NM_000112.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.86
• Publications: 9 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 21 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005911657: Experimental studies confirmed its pathogenic effect on the protein. It reduced the transportation of sulfates and oxalates, and also reduced the surface abundance of the protein.; SCV001588933: Experimental studies have shown that this variant affects SLC26A2 protein function (PMID: 20219950, 23369989).
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-149980750-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1473129.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 5-149980750-C-T is Pathogenic according to our data. Variant chr5-149980750-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 56012.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.1157C>T	p.Ala386Val	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.1157C>T	p.Ala386Val	missense	Exon 3 of 3	ENSP00000286298.4	P50443
	SLC26A2	ENST00000862081.1		c.1157C>T	p.Ala386Val	missense	Exon 4 of 4	ENSP00000532140.1
	SLC26A2	ENST00000862082.1		c.1157C>T	p.Ala386Val	missense	Exon 3 of 3	ENSP00000532141.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Diastrophic dysplasia (2)
1	-	-	Achondrogenesis, type IB (1)
1	-	-	Diastrophic dysplasia;C0265274:Achondrogenesis, type IB;C1847593:Multiple epiphyseal dysplasia type 4;C1850554:Atelosteogenesis type II (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.9
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.88
gMVP		0.96
Mutation Taster		=6/94	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

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

Other links and lift over

dbSNP: rs386833493; hg19: chr5-149360313;