rs1046089

Positions:

• chr6-31635190-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_004638.4(PRRC2A):​c.5219G>A​(p.Arg1740His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.358 in 1,613,872 control chromosomes in the GnomAD database, including 106,562 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.40 (12571 hom., cov: 32)
  • Exomes 𝑓: 0.35 (93991 hom.)
• Consequence: PRRC2A NM_004638.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 3.41

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]

PRRC2A (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.2975626E-4).
• BP6: Variant 6-31635190-G-A is Benign according to our data. Variant chr6-31635190-G-A is described in ClinVar as [Benign]. Clinvar id is 3060262.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.497 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRRC2A	NM_004638.4	c.5219G>A	p.Arg1740His	missense_variant	22/31	ENST00000376033.3	NP_004629.3
PRRC2A	NM_080686.3	c.5219G>A	p.Arg1740His	missense_variant	22/31		NP_542417.2
PRRC2A	XM_047419336.1	c.5219G>A	p.Arg1740His	missense_variant	22/30		XP_047275292.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRRC2A	ENST00000376033.3	c.5219G>A	p.Arg1740His	missense_variant	22/31	1	NM_004638.4	ENSP00000365201.2
PRRC2A	ENST00000376007.8	c.5219G>A	p.Arg1740His	missense_variant	22/31	1		ENSP00000365175.4
PRRC2A	ENST00000484787.1	n.630G>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.399 AC: 60663 AN: 151920 Hom.: 12565 Cov.: 32

Gnomad AFR AF: 0.503

Gnomad AMI AF: 0.327

Gnomad AMR AF: 0.366

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.366

Gnomad SAS AF: 0.293

Gnomad FIN AF: 0.499

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.360

GnomAD3 exomes AF: 0.357 AC: 89663 AN: 251378 Hom.: 16895 AF XY: 0.346 AC XY: 47035 AN XY: 135868

Gnomad AFR exome AF: 0.513

Gnomad AMR exome AF: 0.383

Gnomad ASJ exome AF: 0.193

Gnomad EAS exome AF: 0.385

Gnomad SAS exome AF: 0.266

Gnomad FIN exome AF: 0.476

Gnomad NFE exome AF: 0.339

Gnomad OTH exome AF: 0.332

GnomAD4 exome AF: 0.354 AC: 517868 AN: 1461834 Hom.: 93991 Cov.: 68 AF XY: 0.349 AC XY: 253786 AN XY: 727212

Gnomad4 AFR exome AF: 0.514

Gnomad4 AMR exome AF: 0.380

Gnomad4 ASJ exome AF: 0.202

Gnomad4 EAS exome AF: 0.369

Gnomad4 SAS exome AF: 0.272

Gnomad4 FIN exome AF: 0.476

Gnomad4 NFE exome AF: 0.353

Gnomad4 OTH exome AF: 0.349

GnomAD4 genome AF: 0.399 AC: 60700 AN: 152038 Hom.: 12571 Cov.: 32 AF XY: 0.402 AC XY: 29892 AN XY: 74310

Gnomad4 AFR AF: 0.503

Gnomad4 AMR AF: 0.367

Gnomad4 ASJ AF: 0.195

Gnomad4 EAS AF: 0.366

Gnomad4 SAS AF: 0.293

Gnomad4 FIN AF: 0.499

Gnomad4 NFE AF: 0.351

Gnomad4 OTH AF: 0.359

Alfa AF: 0.351 Hom.: 20322

Bravo AF: 0.397

TwinsUK AF: 0.351 AC: 1300

ALSPAC AF: 0.348 AC: 1343

ESP6500AA AF: 0.510 AC: 2245

ESP6500EA AF: 0.345 AC: 2971

ExAC AF: 0.357 AC: 43360

Asia WGS AF: 0.339 AC: 1178 AN: 3478

EpiCase AF: 0.324

EpiControl AF: 0.318

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PRRC2A-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 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
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.026	T;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.73	.;T
MetaRNN	Benign	0.00083	T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.90	L;L
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.15
Sift	Benign	0.053	T;T
Sift4G	Uncertain	0.029	D;D
Polyphen		0.96	D;D
Vest4		0.19
MPC		0.20
ClinPred		0.012	T
GERP RS		5.5
Varity_R		0.13
gMVP		0.35

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: rs1046089; hg19: chr6-31602967; COSMIC: COSV52990077; COSMIC: COSV52990077;