Genetic Variant C2orf81:p.Gly323Glu (chr2-74415209-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001316764.3(C2orf81):c.968G>A(p.Gly323Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000433 in 1,548,656 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000043 ( 1 hom. )

Consequence

C2orf81
NM_001316764.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.959

Variant links:

Genes affected

C2orf81 (HGNC:34350): (chromosome 2 open reading frame 81) Predicted to be involved in regulation of transcription, DNA-templated. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

C2orf81 links:

ENSG00000159239 (HGNC:):

ENSG00000159239 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.015669793).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C2orf81	NM_001316764.3 link	c.968G>A	p.Gly323Glu	missense_variant	Exon 3 of 3	ENST00000684111.1	NP_001303693.1	A0A804HJ35
C2orf81	NM_001145054.2 link	c.887G>A	p.Gly296Glu	missense_variant	Exon 4 of 4		NP_001138526.1	G3XAA6
C2orf81	NM_001316765.2 link	c.821G>A	p.Gly274Glu	missense_variant	Exon 3 of 3		NP_001303694.1
C2orf81	NM_001316766.2 link	c.683G>A	p.Gly228Glu	missense_variant	Exon 2 of 2		NP_001303695.1	A0A1W2PQG2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C2orf81	ENST00000684111.1 link	c.968G>A	p.Gly323Glu	missense_variant	Exon 3 of 3		NM_001316764.3	ENSP00000507340.1		A0A804HJ35
ENSG00000159239	ENST00000517883.2 link	n.683G>A		non_coding_transcript_exon_variant	Exon 2 of 5	5		ENSP00000431103.2		E5RJQ4

Frequencies

GnomAD3 genomes

AF:

0.0000465

AC:

AN:

150562

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000916

AC:

AN:

152758

Hom.:

AF XY:

0.000123

AC XY:

AN XY:

81356

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000952

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000102

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000429

AC:

AN:

1398094

Hom.:

Cov.:

AF XY:

0.0000450

AC XY:

AN XY:

689552

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000281

Gnomad4 ASJ exome

AF:

0.00119

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000176

Gnomad4 OTH exome

AF:

0.000155

GnomAD4 genome

AF:

0.0000465

AC:

AN:

150562

Hom.:

Cov.:

AF XY:

0.0000544

AC XY:

AN XY:

73516

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000158

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000406

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.887G>A (p.G296E) alteration is located in exon 4 (coding exon 4) of the C2orf81 gene. This alteration results from a G to A substitution at nucleotide position 887, causing the glycine (G) at amino acid position 296 to be replaced by a glutamic acid (E). 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

0.098

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.69

CADD

Benign

2.1

DANN

Benign

0.67

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0060

LIST_S2

Benign

0.45

T;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.016

T;T;T

MetaSVM

Benign

-1.0

PROVEAN

Benign

-0.53

.;.;N

REVEL

Benign

0.039

Sift

Benign

0.61

.;.;T

Sift4G

Benign

1.0

T;.;T

Polyphen

0.015

.;.;B

Vest4

0.050

MutPred

0.33

.;.;Gain of solvent accessibility (P = 0.0456);

MVP

0.067

ClinPred

0.011

GERP RS

-0.96

Varity_R

0.056

gMVP

0.050

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

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