6-31625543-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004638.4(PRRC2A):c.691C>T(p.Pro231Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000704 in 1,575,590 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P231L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: PRRC2A NM_004638.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.81

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06898302).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRRC2A	NM_004638.4	c.691C>T	p.Pro231Ser	missense_variant	7/31	ENST00000376033.3
PRRC2A	NM_080686.3	c.691C>T	p.Pro231Ser	missense_variant	7/31
PRRC2A	XM_047419336.1	c.691C>T	p.Pro231Ser	missense_variant	7/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRRC2A	ENST00000376033.3	c.691C>T	p.Pro231Ser	missense_variant	7/31	1	NM_004638.4	P1
	ENST00000687518.1			downstream_gene_variant				P1

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000129 AC: 29 AN: 224380 Hom.: 0 AF XY: 0.0000833 AC XY: 10 AN XY: 120072

Gnomad AFR exome AF: 0.000942

Gnomad AMR exome AF: 0.000443

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000436 AC: 62 AN: 1423410 Hom.: 0 Cov.: 33 AF XY: 0.0000327 AC XY: 23 AN XY: 702882

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.000480

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000124

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000102

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.000256 AC XY: 19 AN XY: 74340

Gnomad4 AFR AF: 0.000917

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00287

Alfa AF: 0.0000737 Hom.: 0

Bravo AF: 0.000495

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000124 AC: 15

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 26, 2023

The c.691C>T (p.P231S) alteration is located in exon 7 (coding exon 6) of the PRRC2A gene. This alteration results from a C to T substitution at nucleotide position 691, causing the proline (P) at amino acid position 231 to be replaced by a serine (S). 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	Benign	0.072
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0060	T;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.069	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.15
Sift	Benign	0.068	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.99	D;D
Vest4		0.15
MVP		0.10
MPC		0.16
ClinPred		0.048	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.069
gMVP		0.40

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: rs148710175; hg19: chr6-31593320; COSMIC: COSV99057844; COSMIC: COSV99057844;