6-31625488-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000687518.1(ENSG00000289282):c.382G>T(p.Ala128Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0386 in 1,588,870 control chromosomes in the GnomAD database, including 1,355 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A128V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.030 (99 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1256 hom.)
• Consequence: ENST00000687518.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.999

Genes affected

(HGNC:):

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 6-31625488-G-T is Benign according to our data. Variant chr6-31625488-G-T is described in ClinVar as [Benign]. Clinvar id is 3056017.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0301 (4589/152286) while in subpopulation NFE AF= 0.0462 (3141/68008). AF 95% confidence interval is 0.0448. There are 99 homozygotes in gnomad4. There are 2142 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 99 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRRC2A	NM_004638.4	c.636G>T	p.Gly212=	synonymous_variant	7/31	ENST00000376033.3
PRRC2A	NM_080686.3	c.636G>T	p.Gly212=	synonymous_variant	7/31
PRRC2A	XM_047419336.1	c.636G>T	p.Gly212=	synonymous_variant	7/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
	ENST00000687518.1	c.382G>T	p.Ala128Ser	missense_variant	5/5			P1
PRRC2A	ENST00000376033.3	c.636G>T	p.Gly212=	synonymous_variant	7/31	1	NM_004638.4	P1

Frequencies

GnomAD3 genomes AF: 0.0302 AC: 4589 AN: 152168 Hom.: 99 Cov.: 32

Gnomad AFR AF: 0.00671

Gnomad AMI AF: 0.0516

Gnomad AMR AF: 0.0278

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.00423

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.0438

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0462

Gnomad OTH AF: 0.0311

GnomAD3 exomes AF: 0.0319 AC: 7545 AN: 236408 Hom.: 171 AF XY: 0.0332 AC XY: 4205 AN XY: 126714

Gnomad AFR exome AF: 0.00532

Gnomad AMR exome AF: 0.0174

Gnomad ASJ exome AF: 0.0166

Gnomad EAS exome AF: 0.00453

Gnomad SAS exome AF: 0.0212

Gnomad FIN exome AF: 0.0470

Gnomad NFE exome AF: 0.0462

Gnomad OTH exome AF: 0.0315

GnomAD4 exome AF: 0.0395 AC: 56800 AN: 1436584 Hom.: 1256 Cov.: 33 AF XY: 0.0392 AC XY: 27850 AN XY: 710642

Gnomad4 AFR exome AF: 0.00530

Gnomad4 AMR exome AF: 0.0175

Gnomad4 ASJ exome AF: 0.0159

Gnomad4 EAS exome AF: 0.00562

Gnomad4 SAS exome AF: 0.0207

Gnomad4 FIN exome AF: 0.0481

Gnomad4 NFE exome AF: 0.0446

Gnomad4 OTH exome AF: 0.0344

GnomAD4 genome AF: 0.0301 AC: 4589 AN: 152286 Hom.: 99 Cov.: 32 AF XY: 0.0288 AC XY: 2142 AN XY: 74478

Gnomad4 AFR AF: 0.00669

Gnomad4 AMR AF: 0.0278

Gnomad4 ASJ AF: 0.0159

Gnomad4 EAS AF: 0.00424

Gnomad4 SAS AF: 0.0180

Gnomad4 FIN AF: 0.0438

Gnomad4 NFE AF: 0.0462

Gnomad4 OTH AF: 0.0308

Alfa AF: 0.0376 Hom.: 187

Bravo AF: 0.0271

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PRRC2A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 27, 2019

This variant is classified as 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	-0.56
Cadd	Benign	18
Dann	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9

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

Publications

LitVar

Other links and lift over

dbSNP: rs17200837; hg19: chr6-31593265; COSMIC: COSV63224978; COSMIC: COSV63224978;