rs2736158

chr6-31632527-G-Cchr6-31632527-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004638.4(PRRC2A):c.3854G>C(p.Gly1285Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.04 in 1,609,644 control chromosomes in the GnomAD database, including 2,178 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.066 (509 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1669 hom.)
• Consequence: PRRC2A NM_004638.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.64

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016219318).
• BP6: Variant 6-31632527-G-C is Benign according to our data. Variant chr6-31632527-G-C is described in ClinVar as [Benign]. Clinvar id is 1229769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRRC2A	NM_004638.4	c.3854G>C	p.Gly1285Ala	missense_variant	16/31	ENST00000376033.3
PRRC2A	NM_080686.3	c.3854G>C	p.Gly1285Ala	missense_variant	16/31
PRRC2A	XM_047419336.1	c.3854G>C	p.Gly1285Ala	missense_variant	16/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRRC2A	ENST00000376033.3	c.3854G>C	p.Gly1285Ala	missense_variant	16/31	1	NM_004638.4	P1
PRRC2A	ENST00000376007.8	c.3854G>C	p.Gly1285Ala	missense_variant	16/31	1		P1

Frequencies

GnomAD3 genomes AF: 0.0662 AC: 10070 AN: 152066 Hom.: 509 Cov.: 32

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0614

Gnomad ASJ AF: 0.0498

Gnomad EAS AF: 0.132

Gnomad SAS AF: 0.0599

Gnomad FIN AF: 0.00585

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0288

Gnomad OTH AF: 0.0724

GnomAD3 exomes AF: 0.0489 AC: 11941 AN: 244426 Hom.: 583 AF XY: 0.0473 AC XY: 6305 AN XY: 133188

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.0517

Gnomad ASJ exome AF: 0.0488

Gnomad EAS exome AF: 0.142

Gnomad SAS exome AF: 0.0546

Gnomad FIN exome AF: 0.00464

Gnomad NFE exome AF: 0.0271

Gnomad OTH exome AF: 0.0473

GnomAD4 exome AF: 0.0373 AC: 54378 AN: 1457460 Hom.: 1669 Cov.: 33 AF XY: 0.0374 AC XY: 27084 AN XY: 724604

Gnomad4 AFR exome AF: 0.146

Gnomad4 AMR exome AF: 0.0541

Gnomad4 ASJ exome AF: 0.0512

Gnomad4 EAS exome AF: 0.0977

Gnomad4 SAS exome AF: 0.0541

Gnomad4 FIN exome AF: 0.00608

Gnomad4 NFE exome AF: 0.0298

Gnomad4 OTH exome AF: 0.0511

GnomAD4 genome AF: 0.0662 AC: 10074 AN: 152184 Hom.: 509 Cov.: 32 AF XY: 0.0663 AC XY: 4928 AN XY: 74384

Gnomad4 AFR AF: 0.139

Gnomad4 AMR AF: 0.0613

Gnomad4 ASJ AF: 0.0498

Gnomad4 EAS AF: 0.131

Gnomad4 SAS AF: 0.0597

Gnomad4 FIN AF: 0.00585

Gnomad4 NFE AF: 0.0288

Gnomad4 OTH AF: 0.0721

Alfa AF: 0.0363 Hom.: 153

Bravo AF: 0.0736

TwinsUK AF: 0.0291 AC: 108

ALSPAC AF: 0.0293 AC: 113

ESP6500AA AF: 0.133 AC: 401

ESP6500EA AF: 0.0297 AC: 161

ExAC AF: 0.0482 AC: 5710

Asia WGS AF: 0.0790 AC: 274 AN: 3478

EpiCase AF: 0.0309

EpiControl AF: 0.0319

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 18, 2020

This variant is associated with the following publications: (PMID: 23221128) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	14
Dann	Benign	0.85
DEOGEN2	Benign	0.0031	T;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.69	D
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.061
Sift	Benign	0.14	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;B
Vest4		0.21
MPC		0.17
ClinPred		0.013	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.061
gMVP		0.11

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: rs2736158; hg19: chr6-31600304; COSMIC: COSV65686676; COSMIC: COSV65686676;