6-31625782-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_004638.4(PRRC2A):c.760-10C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,568,688 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (18 hom.)
• Consequence: PRRC2A NM_004638.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.004927
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.145

Genes affected

PRRC2A (HGNC:13918): (proline rich coiled-coil 2A) A cluster of genes, BAT1-BAT5, has been localized in the vicinity of the genes for TNF alpha and TNF beta. These genes are all within the human major histocompatibility complex class III region. This gene has microsatellite repeats which are associated with the age-at-onset of insulin-dependent diabetes mellitus (IDDM) and possibly thought to be involved with the inflammatory process of pancreatic beta-cell destruction during the development of IDDM. This gene is also a candidate gene for the development of rheumatoid arthritis. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Dec 2010]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 6-31625782-C-G is Benign according to our data. Variant chr6-31625782-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3042147.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRRC2A	NM_004638.4	c.760-10C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000376033.3
PRRC2A	NM_080686.3	c.760-10C>G		splice_polypyrimidine_tract_variant, intron_variant
PRRC2A	XM_047419336.1	c.760-10C>G		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRRC2A	ENST00000376033.3	c.760-10C>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_004638.4	P1
PRRC2A	ENST00000376007.8	c.760-10C>G		splice_polypyrimidine_tract_variant, intron_variant		1		P1
PRRC2A	ENST00000464890.1	n.29C>G		non_coding_transcript_exon_variant	1/3	2
PRRC2A	ENST00000469577.5	n.605-10C>G		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00198 AC: 301 AN: 152012 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000556

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00309

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00250 AC: 625 AN: 250364 Hom.: 5 AF XY: 0.00269 AC XY: 365 AN XY: 135528

Gnomad AFR exome AF: 0.000623

Gnomad AMR exome AF: 0.00260

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.00310

Gnomad FIN exome AF: 0.00268

Gnomad NFE exome AF: 0.00293

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00267 AC: 3778 AN: 1416558 Hom.: 18 Cov.: 33 AF XY: 0.00276 AC XY: 1951 AN XY: 707120

Gnomad4 AFR exome AF: 0.000340

Gnomad4 AMR exome AF: 0.00275

Gnomad4 ASJ exome AF: 0.00193

Gnomad4 EAS exome AF: 0.000203

Gnomad4 SAS exome AF: 0.00353

Gnomad4 FIN exome AF: 0.00220

Gnomad4 NFE exome AF: 0.00282

Gnomad4 OTH exome AF: 0.00221

GnomAD4 genome AF: 0.00198 AC: 301 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.00184 AC XY: 137 AN XY: 74360

Gnomad4 AFR AF: 0.000555

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.00291

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00309

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00183 Hom.: 1

Bravo AF: 0.00201

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PRRC2A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 05, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
Cadd	Benign	8.2
Dann	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0049
dbscSNV1_RF	Benign	0.048
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs180704814; hg19: chr6-31593559;