rs1046080

Positions:

• chr6-31628105-C-A
• chr6-31628105-C-G

Variant summary

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

The NM_004638.4(PRRC2A):​c.1631C>A​(p.Thr544Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.748 in 1,612,820 control chromosomes in the GnomAD database, including 455,099 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 (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.74 (42349 hom., cov: 31)
  • Exomes 𝑓: 0.75 (412750 hom.)
• Consequence: PRRC2A NM_004638.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.78

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.3481995E-7).
• BP6: Variant 6-31628105-C-A is Benign according to our data. Variant chr6-31628105-C-A is described in ClinVar as [Benign]. Clinvar id is 3060200.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.951 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRRC2A	NM_004638.4	c.1631C>A	p.Thr544Lys	missense_variant	12/31	ENST00000376033.3	NP_004629.3
PRRC2A	NM_080686.3	c.1631C>A	p.Thr544Lys	missense_variant	12/31		NP_542417.2
PRRC2A	XM_047419336.1	c.1631C>A	p.Thr544Lys	missense_variant	12/30		XP_047275292.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRRC2A	ENST00000376033.3	c.1631C>A	p.Thr544Lys	missense_variant	12/31	1	NM_004638.4	ENSP00000365201.2
PRRC2A	ENST00000376007.8	c.1631C>A	p.Thr544Lys	missense_variant	12/31	1		ENSP00000365175.4

Frequencies

GnomAD3 genomes AF: 0.743 AC: 112899 AN: 151872 Hom.: 42320 Cov.: 31

Gnomad AFR AF: 0.668

Gnomad AMI AF: 0.848

Gnomad AMR AF: 0.769

Gnomad ASJ AF: 0.883

Gnomad EAS AF: 0.973

Gnomad SAS AF: 0.839

Gnomad FIN AF: 0.816

Gnomad MID AF: 0.832

Gnomad NFE AF: 0.739

Gnomad OTH AF: 0.755

GnomAD3 exomes AF: 0.792 AC: 195889 AN: 247322 Hom.: 78468 AF XY: 0.791 AC XY: 106472 AN XY: 134644

Gnomad AFR exome AF: 0.668

Gnomad AMR exome AF: 0.849

Gnomad ASJ exome AF: 0.892

Gnomad EAS exome AF: 0.980

Gnomad SAS exome AF: 0.809

Gnomad FIN exome AF: 0.803

Gnomad NFE exome AF: 0.746

Gnomad OTH exome AF: 0.778

GnomAD4 exome AF: 0.749 AC: 1093803 AN: 1460830 Hom.: 412750 Cov.: 93 AF XY: 0.751 AC XY: 545931 AN XY: 726722

Gnomad4 AFR exome AF: 0.667

Gnomad4 AMR exome AF: 0.840

Gnomad4 ASJ exome AF: 0.889

Gnomad4 EAS exome AF: 0.982

Gnomad4 SAS exome AF: 0.810

Gnomad4 FIN exome AF: 0.796

Gnomad4 NFE exome AF: 0.728

Gnomad4 OTH exome AF: 0.760

GnomAD4 genome AF: 0.743 AC: 112972 AN: 151990 Hom.: 42349 Cov.: 31 AF XY: 0.750 AC XY: 55724 AN XY: 74274

Gnomad4 AFR AF: 0.667

Gnomad4 AMR AF: 0.769

Gnomad4 ASJ AF: 0.883

Gnomad4 EAS AF: 0.973

Gnomad4 SAS AF: 0.839

Gnomad4 FIN AF: 0.816

Gnomad4 NFE AF: 0.739

Gnomad4 OTH AF: 0.759

Alfa AF: 0.760 Hom.: 79598

Bravo AF: 0.737

TwinsUK AF: 0.730 AC: 2705

ALSPAC AF: 0.719 AC: 2772

ESP6500AA AF: 0.684 AC: 2068

ESP6500EA AF: 0.743 AC: 4024

ExAC AF: 0.786 AC: 93014

Asia WGS AF: 0.904 AC: 3141 AN: 3478

EpiCase AF: 0.765

EpiControl AF: 0.767

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 17, 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	0.040
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	14
DANN	Benign	0.90
DEOGEN2	Benign	0.0021	T;T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.066	.;T
MetaRNN	Benign	5.3e-7	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.90	N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	2.3	N;N
REVEL	Benign	0.14
Sift	Benign	0.51	T;T
Sift4G	Benign	0.32	T;T
Polyphen		0.0	B;B
Vest4		0.043
MPC		0.19
ClinPred		0.013	T
GERP RS		4.6
Varity_R		0.028
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1046080; hg19: chr6-31595882;