rs11538264

Variant names:

• chr6-31635412-G-A
• rs11538264
• NM_004638.4:c.5320G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_004638.4(PRRC2A):​c.5320G>A​(p.Val1774Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0258 in 1,614,168 control chromosomes in the GnomAD database, including 1,162 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.045 (271 hom., cov: 33)
  • Exomes 𝑓: 0.024 (891 hom.)
• Consequence: PRRC2A NM_004638.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.22
• Publications: 21 publications found

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019162595).
• BP6: Variant 6-31635412-G-A is Benign according to our data. Variant chr6-31635412-G-A is described in ClinVar as Benign. ClinVar VariationId is 3057120.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0866 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004638.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRRC2A	NM_004638.4	MANE Select	c.5320G>A	p.Val1774Met	missense	Exon 23 of 31	NP_004629.3
	PRRC2A	NM_080686.3		c.5320G>A	p.Val1774Met	missense	Exon 23 of 31	NP_542417.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRRC2A	ENST00000376033.3	TSL:1 MANE Select	c.5320G>A	p.Val1774Met	missense	Exon 23 of 31	ENSP00000365201.2
	PRRC2A	ENST00000376007.8	TSL:1	c.5320G>A	p.Val1774Met	missense	Exon 23 of 31	ENSP00000365175.4
	PRRC2A	ENST00000469501.1	TSL:5	n.50G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.0450 AC: 6857 AN: 152246 Hom.: 268 Cov.: 33

Gnomad AFR AF: 0.0887

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0555

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.0173

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0218

Gnomad OTH AF: 0.0693

GnomAD2 exomes AF: 0.0327 AC: 8221 AN: 251250 AF XY: 0.0299

Gnomad AFR exome AF: 0.0880

Gnomad AMR exome AF: 0.0523

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.0134

Gnomad FIN exome AF: 0.00263

Gnomad NFE exome AF: 0.0219

Gnomad OTH exome AF: 0.0466

GnomAD4 exome AF: 0.0238 AC: 34792 AN: 1461804 Hom.: 891 Cov.: 35 AF XY: 0.0236 AC XY: 17128 AN XY: 727208

African (AFR) AF: 0.0885 AC: 2964 AN: 33476

American (AMR) AF: 0.0531 AC: 2376 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 3653 AN: 26128

East Asian (EAS) AF: 0.0449 AC: 1782 AN: 39700

South Asian (SAS) AF: 0.0163 AC: 1407 AN: 86256

European-Finnish (FIN) AF: 0.00279 AC: 149 AN: 53420

Middle Eastern (MID) AF: 0.0680 AC: 392 AN: 5768

European-Non Finnish (NFE) AF: 0.0178 AC: 19841 AN: 1111940

Other (OTH) AF: 0.0369 AC: 2228 AN: 60394

GnomAD4 genome AF: 0.0451 AC: 6876 AN: 152364 Hom.: 271 Cov.: 33 AF XY: 0.0439 AC XY: 3271 AN XY: 74512

African (AFR) AF: 0.0890 AC: 3700 AN: 41576

American (AMR) AF: 0.0555 AC: 850 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 488 AN: 3472

East Asian (EAS) AF: 0.0173 AC: 90 AN: 5192

South Asian (SAS) AF: 0.0170 AC: 82 AN: 4828

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10632

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0218 AC: 1480 AN: 68040

Other (OTH) AF: 0.0686 AC: 145 AN: 2114

Alfa AF: 0.0349 Hom.: 511

Bravo AF: 0.0516

TwinsUK AF: 0.0162 AC: 60

ALSPAC AF: 0.0179 AC: 69

ESP6500AA AF: 0.0850 AC: 257

ESP6500EA AF: 0.0271 AC: 147

ExAC AF: 0.0312 AC: 3791

Asia WGS AF: 0.0250 AC: 86 AN: 3478

EpiCase AF: 0.0282

EpiControl AF: 0.0302

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PRRC2A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	18
DANN	Benign	0.85
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.2
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.073
Sift	Benign	0.045	D
Sift4G	Benign	0.086	T
Polyphen		0.0030	B
Vest4		0.12
MPC		0.16
ClinPred		0.0038	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.041
gMVP		0.22
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11538264; hg19: chr6-31603189; COSMIC: COSV52990179; COSMIC: COSV52990179;