chr5-149981515-A-G

Variant names:

• chr5-149981515-A-G
• rs1253691463
• NM_000112.4:c.1922A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_000112.4(SLC26A2):​c.1922A>G​(p.His641Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: SLC26A2 NM_000112.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.145
• Publications: 2 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, Ambry Genetics, G2P, ClinGen
• atelosteogenesis type II

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

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 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
• PM2: Very rare variant in population databases, with high coverage
• 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=0.22363704).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A2	NM_000112.4	MANE Select	c.1922A>G	p.His641Arg	missense	Exon 3 of 3	NP_000103.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A2	ENST00000286298.5	TSL:1 MANE Select	c.1922A>G	p.His641Arg	missense	Exon 3 of 3	ENSP00000286298.4
	SLC26A2	ENST00000503336.1	TSL:3	c.372+3164A>G		intron	N/A	ENSP00000426053.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251308 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461854 Hom.: 0 Cov.: 34 AF XY: 0.0000151 AC XY: 11 AN XY: 727222

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1111984

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Multiple epiphyseal dysplasia type 4 Uncertain:1

Feb 07, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.68
DANN	Benign	0.71
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.14
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.042
Sift	Benign	0.59	T
Sift4G	Benign	0.52	T
Polyphen		0.045	B
Vest4		0.64
MutPred		0.34		Loss of catalytic residue at D642 (P = 0.094)
MVP		0.68
MPC		0.054
ClinPred		0.057	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.064
gMVP		0.31
Mutation Taster		=94/6	polymorphism

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: rs1253691463; hg19: chr5-149361078; COSMIC: COSV99640276; COSMIC: COSV99640276;