rs10885

Positions:

• chr6-31636814-C-T

Variant summary

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

The NM_004638.4(PRRC2A):​c.6016C>T​(p.Pro2006Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 1,610,838 control chromosomes in the GnomAD database, including 26,622 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 0.17 (2380 hom., cov: 32)
  • Exomes 𝑓: 0.18 (24242 hom.)
• Consequence: PRRC2A NM_004638.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 3.57

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=0.0016311109).
• BP6: Variant 6-31636814-C-T is Benign according to our data. Variant chr6-31636814-C-T is described in ClinVar as [Benign]. Clinvar id is 3058971.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRRC2A	NM_004638.4	c.6016C>T	p.Pro2006Ser	missense_variant	28/31	ENST00000376033.3	NP_004629.3
PRRC2A	NM_080686.3	c.6016C>T	p.Pro2006Ser	missense_variant	28/31		NP_542417.2
PRRC2A	XM_047419336.1	c.5934+206C>T		intron_variant			XP_047275292.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRRC2A	ENST00000376033.3	c.6016C>T	p.Pro2006Ser	missense_variant	28/31	1	NM_004638.4	ENSP00000365201.2

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25650 AN: 152060 Hom.: 2380 Cov.: 32

Gnomad AFR AF: 0.193

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.0988

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.0785

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.150

GnomAD3 exomes AF: 0.145 AC: 35394 AN: 244646 Hom.: 2907 AF XY: 0.145 AC XY: 19381 AN XY: 133638

Gnomad AFR exome AF: 0.197

Gnomad AMR exome AF: 0.0767

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.0960

Gnomad SAS exome AF: 0.109

Gnomad FIN exome AF: 0.160

Gnomad NFE exome AF: 0.177

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.176 AC: 256955 AN: 1458660 Hom.: 24242 Cov.: 51 AF XY: 0.174 AC XY: 126120 AN XY: 725806

Gnomad4 AFR exome AF: 0.206

Gnomad4 AMR exome AF: 0.0803

Gnomad4 ASJ exome AF: 0.119

Gnomad4 EAS exome AF: 0.0467

Gnomad4 SAS exome AF: 0.115

Gnomad4 FIN exome AF: 0.161

Gnomad4 NFE exome AF: 0.192

Gnomad4 OTH exome AF: 0.165

GnomAD4 genome AF: 0.169 AC: 25650 AN: 152178 Hom.: 2380 Cov.: 32 AF XY: 0.164 AC XY: 12212 AN XY: 74402

Gnomad4 AFR AF: 0.193

Gnomad4 AMR AF: 0.0985

Gnomad4 ASJ AF: 0.115

Gnomad4 EAS AF: 0.0791

Gnomad4 SAS AF: 0.124

Gnomad4 FIN AF: 0.161

Gnomad4 NFE AF: 0.184

Gnomad4 OTH AF: 0.149

Alfa AF: 0.175 Hom.: 2304

Bravo AF: 0.166

TwinsUK AF: 0.190 AC: 706

ALSPAC AF: 0.193 AC: 744

ESP6500AA AF: 0.196 AC: 590

ESP6500EA AF: 0.176 AC: 955

ExAC AF: 0.148 AC: 17367

Asia WGS AF: 0.0950 AC: 331 AN: 3478

EpiCase AF: 0.173

EpiControl AF: 0.165

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	0.16
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.094	T;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.69	.;T
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.97	D;D
Vest4		0.17
MPC		0.16
ClinPred		0.034	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.53

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: rs10885; hg19: chr6-31604591; COSMIC: COSV52988962; COSMIC: COSV52988962;