NM_000112.4:c.1721T>C

Variant names:

• chr5-149981314-T-C
• rs30832
• NM_000112.4:c.1721T>C

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.1721T>C​(p.Ile574Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.99 in 1,614,158 control chromosomes in the GnomAD database, including 791,001 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (75125 hom., cov: 32)
  • Exomes 𝑓: 0.99 (715876 hom.)
• Consequence: SLC26A2 NM_000112.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 1.69
• Publications: 38 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=2.4856772E-6).
• BP6: Variant 5-149981314-T-C is Benign according to our data. Variant chr5-149981314-T-C is described in ClinVar as Benign. ClinVar VariationId is 196209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.99 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.1721T>C	p.Ile574Thr	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.1721T>C	p.Ile574Thr	missense	Exon 3 of 3	ENSP00000286298.4	P50443
	SLC26A2	ENST00000862081.1		c.1721T>C	p.Ile574Thr	missense	Exon 4 of 4	ENSP00000532140.1
	SLC26A2	ENST00000862082.1		c.1721T>C	p.Ile574Thr	missense	Exon 3 of 3	ENSP00000532141.1

Frequencies

GnomAD3 genomes AF: 0.993 AC: 151159 AN: 152200 Hom.: 75063 Cov.: 32

Gnomad AFR AF: 0.998

Gnomad AMI AF: 0.993

Gnomad AMR AF: 0.995

Gnomad ASJ AF: 0.993

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.993

Gnomad FIN AF: 0.998

Gnomad MID AF: 0.984

Gnomad NFE AF: 0.988

Gnomad OTH AF: 0.994

GnomAD2 exomes AF: 0.993 AC: 249577 AN: 251316 AF XY: 0.993

Gnomad AFR exome AF: 0.998

Gnomad AMR exome AF: 0.997

Gnomad ASJ exome AF: 0.993

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.998

Gnomad NFE exome AF: 0.989

Gnomad OTH exome AF: 0.993

GnomAD4 exome AF: 0.990 AC: 1446695 AN: 1461840 Hom.: 715876 Cov.: 65 AF XY: 0.990 AC XY: 719789 AN XY: 727216

African (AFR) AF: 0.998 AC: 33422 AN: 33480

American (AMR) AF: 0.997 AC: 44607 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.993 AC: 25941 AN: 26134

East Asian (EAS) AF: 1.00 AC: 39696 AN: 39698

South Asian (SAS) AF: 0.995 AC: 85789 AN: 86256

European-Finnish (FIN) AF: 0.997 AC: 53256 AN: 53410

Middle Eastern (MID) AF: 0.997 AC: 5751 AN: 5768

European-Non Finnish (NFE) AF: 0.988 AC: 1098362 AN: 1111976

Other (OTH) AF: 0.991 AC: 59871 AN: 60394

GnomAD4 genome AF: 0.993 AC: 151280 AN: 152318 Hom.: 75125 Cov.: 32 AF XY: 0.993 AC XY: 74005 AN XY: 74490

African (AFR) AF: 0.998 AC: 41477 AN: 41556

American (AMR) AF: 0.995 AC: 15216 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.993 AC: 3447 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5190 AN: 5190

South Asian (SAS) AF: 0.993 AC: 4797 AN: 4830

European-Finnish (FIN) AF: 0.998 AC: 10600 AN: 10618

Middle Eastern (MID) AF: 0.990 AC: 291 AN: 294

European-Non Finnish (NFE) AF: 0.988 AC: 67253 AN: 68038

Other (OTH) AF: 0.995 AC: 2103 AN: 2114

Alfa AF: 0.991 Hom.: 213554

Bravo AF: 0.993

TwinsUK AF: 0.987 AC: 3660

ALSPAC AF: 0.987 AC: 3804

ESP6500AA AF: 0.998 AC: 4397

ESP6500EA AF: 0.991 AC: 8519

ExAC AF: 0.993 AC: 120534

Asia WGS AF: 0.997 AC: 3469 AN: 3478

EpiCase AF: 0.990

EpiControl AF: 0.990

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Achondrogenesis, type IB (2)
-	-	2	not provided (2)
-	-	1	Atelosteogenesis type II (1)
-	-	1	Connective tissue disorder (1)
-	-	1	Diastrophic dysplasia (1)
-	-	1	Diastrophic dysplasia;C0265274:Achondrogenesis, type IB;C1847593:Multiple epiphyseal dysplasia type 4;C1850554:Atelosteogenesis type II (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
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	11
DANN	Benign	0.14
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.0099	T
MetaRNN	Benign	0.0000025	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.6	N
PhyloP100		1.7
PrimateAI	Benign	0.36	T
PROVEAN	Benign	2.9	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.026
MPC		0.055
ClinPred		0.00055	T
GERP RS		4.4
Varity_R		0.034
gMVP		0.20
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: rs30832; hg19: chr5-149360877; COSMIC: COSV107262240; COSMIC: COSV107262240;