10-87660116-C-G

Variant names:

• chr10-87660116-C-G
• rs2255682
• NM_001015880.2:c.27+108C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001015880.2(PAPSS2):​c.27+108C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 1,152,714 control chromosomes in the GnomAD database, including 76,214 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8790 hom., cov: 31)
  • Exomes 𝑓: 0.36 (67424 hom.)
• Consequence: PAPSS2 NM_001015880.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.10
• Publications: 4 publications found

Genes affected

PAPSS2 (HGNC:8604): (3'-phosphoadenosine 5'-phosphosulfate synthase 2) Sulfation is a common modification of endogenous (lipids, proteins, and carbohydrates) and exogenous (xenobiotics and drugs) compounds. In mammals, the sulfate source is 3'-phosphoadenosine 5'-phosphosulfate (PAPS), created from ATP and inorganic sulfate. Two different tissue isoforms encoded by different genes synthesize PAPS. This gene encodes one of the two PAPS synthetases. Defects in this gene cause the Pakistani type of spondyloepimetaphyseal dysplasia. Two alternatively spliced transcript variants that encode different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

PAPSS2 Gene-Disease associations (from GenCC):

• spondyloepimetaphyseal dysplasia, PAPSS2 type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
• autosomal recessive brachyolmia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000196566 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 10-87660116-C-G is Benign according to our data. Variant chr10-87660116-C-G is described in ClinVar as [Benign]. Clinvar id is 1233069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAPSS2	NM_001015880.2	c.27+108C>G		intron_variant	Intron 1 of 12	ENST00000456849.2	NP_001015880.1
PAPSS2	NM_004670.4	c.27+108C>G		intron_variant	Intron 1 of 11		NP_004661.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAPSS2	ENST00000456849.2	c.27+108C>G		intron_variant	Intron 1 of 12	1	NM_001015880.2	ENSP00000406157.1

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50775 AN: 151854 Hom.: 8785 Cov.: 31

Gnomad AFR AF: 0.315

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.0784

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.310

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.387

Gnomad OTH AF: 0.326

GnomAD4 exome AF: 0.357 AC: 357206 AN: 1000744 Hom.: 67424 AF XY: 0.352 AC XY: 179444 AN XY: 510070

African (AFR) AF: 0.308 AC: 7473 AN: 24224

American (AMR) AF: 0.279 AC: 9938 AN: 35560

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 7499 AN: 22660

East Asian (EAS) AF: 0.0679 AC: 2333 AN: 34366

South Asian (SAS) AF: 0.205 AC: 14706 AN: 71878

European-Finnish (FIN) AF: 0.315 AC: 15014 AN: 47678

Middle Eastern (MID) AF: 0.281 AC: 1071 AN: 3806

European-Non Finnish (NFE) AF: 0.397 AC: 283927 AN: 715658

Other (OTH) AF: 0.339 AC: 15245 AN: 44914

GnomAD4 genome AF: 0.334 AC: 50802 AN: 151970 Hom.: 8790 Cov.: 31 AF XY: 0.325 AC XY: 24166 AN XY: 74310

African (AFR) AF: 0.315 AC: 13072 AN: 41454

American (AMR) AF: 0.304 AC: 4644 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.318 AC: 1102 AN: 3470

East Asian (EAS) AF: 0.0786 AC: 404 AN: 5140

South Asian (SAS) AF: 0.202 AC: 975 AN: 4816

European-Finnish (FIN) AF: 0.310 AC: 3272 AN: 10568

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.387 AC: 26256 AN: 67932

Other (OTH) AF: 0.324 AC: 683 AN: 2110

Alfa AF: 0.352 Hom.: 1201

Bravo AF: 0.333

Asia WGS AF: 0.178 AC: 620 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 27, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.14
DANN	Benign	0.69
PhyloP100		-2.1
PromoterAI		-0.070	Neutral
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: rs2255682; hg19: chr10-89419873;