Variant 6-31625522-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004638.4(PRRC2A):c.670A>C(p.Lys224Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,428,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

PRRC2A
NM_004638.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.97

Variant links:

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 links:

PRRC2A (HGNC:):

PRRC2A links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30372077).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRRC2A	NM_004638.4 linkuse as main transcript	c.670A>C	p.Lys224Gln	missense_variant	7/31	ENST00000376033.3	NP_004629.3	P48634-1A0A1U9X974
PRRC2A	NM_080686.3 linkuse as main transcript	c.670A>C	p.Lys224Gln	missense_variant	7/31		NP_542417.2	P48634-1A0A1U9X974
PRRC2A	XM_047419336.1 linkuse as main transcript	c.670A>C	p.Lys224Gln	missense_variant	7/30		XP_047275292.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRRC2A	ENST00000376033.3 linkuse as main transcript	c.670A>C	p.Lys224Gln	missense_variant	7/31	1	NM_004638.4	ENSP00000365201.2		P48634-1
ENSG00000289282	ENST00000687518.1 linkuse as main transcript	c.*23A>C		downstream_gene_variant				ENSP00000509222.1		A0A8I5QKQ9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000434

AC:

AN:

230622

Hom.:

AF XY:

0.00000810

AC XY:

AN XY:

123506

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000954

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.00e-7

AC:

AN:

1428984

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

706154

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.16e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2022

The c.670A>C (p.K224Q) alteration is located in exon 7 (coding exon 6) of the PRRC2A gene. This alteration results from a A to C substitution at nucleotide position 670, causing the lysine (K) at amino acid position 224 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

Benign

0.17

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.0053

T;T

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.84

.;T

M_CAP

Benign

0.0070

MetaRNN

Benign

0.30

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.3

L;L

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.83

N;N

REVEL

Benign

0.11

Sift

Benign

0.10

T;T

Sift4G

Benign

0.18

T;T

Polyphen

1.0

D;D

Vest4

0.48

MutPred

0.19

Loss of ubiquitination at K224 (P = 6e-04);Loss of ubiquitination at K224 (P = 6e-04);

MVP

0.12

MPC

0.17

ClinPred

0.33

GERP RS

5.0

Varity_R

0.10

gMVP

0.19

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over