12-90971906-C-G

Variant names:

• chr12-90971906-C-G
• rs745867926
• NM_004950.5:c.596G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004950.5(EPYC):​c.596G>C​(p.Arg199Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,459,904 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R199H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: EPYC NM_004950.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.26
• Publications: 0 publications found

Genes affected

EPYC (HGNC:3053): (epiphycan) Dermatan sulfate proteoglycan 3 is a member of the small leucine-rich repeat proteoglycan family. This gene is composed of seven exons. It regulates fibrillogenesis by interacting with collagen fibrils and other extracellular matrix proteins. [provided by RefSeq, Jul 2008]

EPYC Gene-Disease associations (from GenCC):

• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004950.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPYC	NM_004950.5	MANE Select	c.596G>C	p.Arg199Pro	missense	Exon 5 of 7	NP_004941.2	Q99645

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPYC	ENST00000261172.8	TSL:1 MANE Select	c.596G>C	p.Arg199Pro	missense	Exon 5 of 7	ENSP00000261172.3	Q99645
	EPYC	ENST00000551767.1	TSL:3	c.596G>C	p.Arg199Pro	missense	Exon 5 of 5	ENSP00000448272.1	F8VSI4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459904 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726292

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44352

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39538

South Asian (SAS) AF: 0.00 AC: 0 AN: 86046

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111060

Other (OTH) AF: 0.00 AC: 0 AN: 60268

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.018	T
Eigen	Benign	0.058
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.3	L
PhyloP100		4.3
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.26
Sift	Benign	0.37	T
Sift4G	Benign	0.29	T
Polyphen		0.052	B
Vest4		0.83
MutPred		0.57		Gain of catalytic residue at L198 (P = 0.009)
MVP		0.75
MPC		0.031
ClinPred		0.94	D
GERP RS		6.0
Varity_R		0.34
gMVP		0.88
Mutation Taster		=51/49	polymorphism

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

Other links and lift over

dbSNP: rs745867926; hg19: chr12-91365683; COSMIC: COSV53800078; COSMIC: COSV53800078;