6-31624305-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004638.4(PRRC2A):c.335C>A(p.Pro112Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000985 in 1,613,992 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00089 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (3 hom.)
• Consequence: PRRC2A NM_004638.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.703

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019969195).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRRC2A	NM_004638.4	c.335C>A	p.Pro112Gln	missense_variant	4/31	ENST00000376033.3
PRRC2A	NM_080686.3	c.335C>A	p.Pro112Gln	missense_variant	4/31
PRRC2A	XM_047419336.1	c.335C>A	p.Pro112Gln	missense_variant	4/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRRC2A	ENST00000376033.3	c.335C>A	p.Pro112Gln	missense_variant	4/31	1	NM_004638.4	P1
PRRC2A	ENST00000376007.8	c.335C>A	p.Pro112Gln	missense_variant	4/31	1		P1
	ENST00000687518.1	c.81C>A	p.Ala27=	synonymous_variant	2/5			P1
PRRC2A	ENST00000469577.5	n.180C>A		non_coding_transcript_exon_variant	2/8	5

Frequencies

GnomAD3 genomes AF: 0.000887 AC: 135 AN: 152214 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00140

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000905 AC: 226 AN: 249650 Hom.: 1 AF XY: 0.000991 AC XY: 134 AN XY: 135254

Gnomad AFR exome AF: 0.000255

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00170

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000653

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00133

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.000995 AC: 1455 AN: 1461660 Hom.: 3 Cov.: 33 AF XY: 0.00101 AC XY: 733 AN XY: 727118

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00218

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000568

Gnomad4 FIN exome AF: 0.000601

Gnomad4 NFE exome AF: 0.00111

Gnomad4 OTH exome AF: 0.000977

GnomAD4 genome AF: 0.000886 AC: 135 AN: 152332 Hom.: 1 Cov.: 33 AF XY: 0.000940 AC XY: 70 AN XY: 74498

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00140

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000949 Hom.: 0

Bravo AF: 0.000914

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000923 AC: 5

ExAC AF: 0.000939 AC: 114

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00158

EpiControl AF: 0.00101

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2022

The c.335C>A (p.P112Q) alteration is located in exon 4 (coding exon 3) of the PRRC2A gene. This alteration results from a C to A substitution at nucleotide position 335, causing the proline (P) at amino acid position 112 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	23
Dann	Benign	0.93
DEOGEN2	Benign	0.025	T;T
Eigen	Benign	0.18
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.020	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Benign	0.14
Sift	Benign	0.095	T;T
Sift4G	Uncertain	0.016	D;D
Polyphen		0.96	D;D
Vest4		0.26
MVP		0.093
MPC		0.89
ClinPred		0.039	T
GERP RS		3.0
Varity_R		0.21
gMVP		0.32

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: rs114928949; hg19: chr6-31592082;