rs11538264

Positions:

• chr6-31635412-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004638.4(PRRC2A):​c.5320G>A​(p.Val1774Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0258 in 1,614,168 control chromosomes in the GnomAD database, including 1,162 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.045 (271 hom., cov: 33)
  • Exomes 𝑓: 0.024 (891 hom.)
• Consequence: PRRC2A NM_004638.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.22

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019162595).
• BP6: Variant 6-31635412-G-A is Benign according to our data. Variant chr6-31635412-G-A is described in ClinVar as [Benign]. Clinvar id is 3057120.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0866 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRRC2A	NM_004638.4	c.5320G>A	p.Val1774Met	missense_variant	23/31	ENST00000376033.3
PRRC2A	NM_080686.3	c.5320G>A	p.Val1774Met	missense_variant	23/31
PRRC2A	XM_047419336.1	c.5320G>A	p.Val1774Met	missense_variant	23/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRRC2A	ENST00000376033.3	c.5320G>A	p.Val1774Met	missense_variant	23/31	1	NM_004638.4	P1

Frequencies

GnomAD3 genomes AF: 0.0450 AC: 6857 AN: 152246 Hom.: 268 Cov.: 33

Gnomad AFR AF: 0.0887

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0555

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.0173

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0218

Gnomad OTH AF: 0.0693

GnomAD3 exomes AF: 0.0327 AC: 8221 AN: 251250 Hom.: 314 AF XY: 0.0299 AC XY: 4062 AN XY: 135856

Gnomad AFR exome AF: 0.0880

Gnomad AMR exome AF: 0.0523

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.0134

Gnomad SAS exome AF: 0.0160

Gnomad FIN exome AF: 0.00263

Gnomad NFE exome AF: 0.0219

Gnomad OTH exome AF: 0.0466

GnomAD4 exome AF: 0.0238 AC: 34792 AN: 1461804 Hom.: 891 Cov.: 35 AF XY: 0.0236 AC XY: 17128 AN XY: 727208

Gnomad4 AFR exome AF: 0.0885

Gnomad4 AMR exome AF: 0.0531

Gnomad4 ASJ exome AF: 0.140

Gnomad4 EAS exome AF: 0.0449

Gnomad4 SAS exome AF: 0.0163

Gnomad4 FIN exome AF: 0.00279

Gnomad4 NFE exome AF: 0.0178

Gnomad4 OTH exome AF: 0.0369

GnomAD4 genome AF: 0.0451 AC: 6876 AN: 152364 Hom.: 271 Cov.: 33 AF XY: 0.0439 AC XY: 3271 AN XY: 74512

Gnomad4 AFR AF: 0.0890

Gnomad4 AMR AF: 0.0555

Gnomad4 ASJ AF: 0.141

Gnomad4 EAS AF: 0.0173

Gnomad4 SAS AF: 0.0170

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.0218

Gnomad4 OTH AF: 0.0686

Alfa AF: 0.0325 Hom.: 281

Bravo AF: 0.0516

TwinsUK AF: 0.0162 AC: 60

ALSPAC AF: 0.0179 AC: 69

ESP6500AA AF: 0.0850 AC: 257

ESP6500EA AF: 0.0271 AC: 147

ExAC AF: 0.0312 AC: 3791

Asia WGS AF: 0.0250 AC: 86 AN: 3478

EpiCase AF: 0.0282

EpiControl AF: 0.0302

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

Jan 14, 2020

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	0.15
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	18
DANN	Benign	0.85
DEOGEN2	Benign	0.014	T;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.80	D
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	0.93	P;P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.88	N;N
REVEL	Benign	0.073
Sift	Benign	0.045	D;D
Sift4G	Benign	0.086	T;T
Polyphen		0.0030	B;B
Vest4		0.12
MPC		0.16
ClinPred		0.0038	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.041
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs11538264; hg19: chr6-31603189; COSMIC: COSV52990179; COSMIC: COSV52990179;