17-38673651-C-G

Variant names:

• chr17-38673651-C-G
• rs1187396238
• NM_001130677.2:c.845G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001130677.2(EPOP):​c.845G>C​(p.Arg282Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000509 in 1,374,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000051 (0 hom.)
• Consequence: EPOP NM_001130677.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.38

Genes affected

EPOP (HGNC:34493): (elongin BC and polycomb repressive complex 2 associated protein) Predicted to enable chromatin binding activity. Predicted to be involved in several processes, including histone H2B conserved C-terminal lysine deubiquitination; neuron fate commitment; and stem cell differentiation. Predicted to be located in chromosome. Predicted to colocalize with ESC/E(Z) complex and elongin complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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=0.3445139).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPOP	NM_001130677.2	c.845G>C	p.Arg282Pro	missense_variant	Exon 1 of 1	ENST00000621654.2	NP_001124149.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPOP	ENST00000621654.2	c.845G>C	p.Arg282Pro	missense_variant	Exon 1 of 1	6	NM_001130677.2	ENSP00000484710.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000509 AC: 7 AN: 1374676 Hom.: 0 Cov.: 37 AF XY: 0.00000590 AC XY: 4 AN XY: 677710

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: 0.00000561

Gnomad4 OTH exome AF: 0.0000176

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.845G>C (p.R282P) alteration is located in exon 1 (coding exon 1) of the C17orf96 gene. This alteration results from a G to C substitution at nucleotide position 845, causing the arginine (R) at amino acid position 282 to be replaced by a proline (P). 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	0.21
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0070	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.22	N
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-1.1	T
Sift4G	Benign	0.26	T
Polyphen		0.99	D
Vest4		0.26
MutPred		0.27		Loss of MoRF binding (P = 6e-04);
MVP		0.35
ClinPred		0.81	D
GERP RS		3.0
Varity_R		0.32
gMVP		0.10

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: rs1187396238; hg19: chr17-36829904;