Genetic Variant NM_001316764.3:c.1231G>A (chr2-74414946-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.1231G>A(p.Gly411Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,546,250 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

C2orf81
NM_001316764.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.71

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=0.041841745).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C2orf81	NM_001316764.3 link	c.1231G>A	p.Gly411Ser	missense_variant	Exon 3 of 3	ENST00000684111.1	NP_001303693.1	A0A804HJ35
C2orf81	NM_001145054.2 link	c.1150G>A	p.Gly384Ser	missense_variant	Exon 4 of 4		NP_001138526.1	G3XAA6
C2orf81	NM_001316765.2 link	c.1084G>A	p.Gly362Ser	missense_variant	Exon 3 of 3		NP_001303694.1
C2orf81	NM_001316766.2 link	c.946G>A	p.Gly316Ser	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.1231G>A	p.Gly411Ser	missense_variant	Exon 3 of 3		NM_001316764.3	ENSP00000507340.1		A0A804HJ35
ENSG00000159239	ENST00000517883.2 link	n.946G>A		non_coding_transcript_exon_variant	Exon 2 of 5	5		ENSP00000431103.2		E5RJQ4

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000543

AC:

AN:

147232

Hom.:

AF XY:

0.0000635

AC XY:

AN XY:

78768

show subpopulations

Gnomad AFR exome

AF:

0.000279

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:

0.0000716

Gnomad NFE exome

AF:

0.0000891

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000147

AC:

205

AN:

1394018

Hom.:

Cov.:

AF XY:

0.000146

AC XY:

100

AN XY:

687130

show subpopulations

Gnomad4 AFR exome

AF:

0.0000635

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:

0.000168

Gnomad4 NFE exome

AF:

0.000174

Gnomad4 OTH exome

AF:

0.000139

GnomAD4 genome

AF:

0.000112

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000220

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000135

Hom.:

Bravo

AF:

0.0000907

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000448

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 22, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1150G>A (p.G384S) 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 1150, causing the glycine (G) at amino acid position 384 to be replaced by a serine (S). 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

0.11

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.25

DANN

Benign

0.73

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.56

T;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.042

T;T;T

MetaSVM

Benign

-1.0

PROVEAN

Benign

-0.070

.;.;N

REVEL

Benign

0.0050

Sift

Benign

0.52

.;.;T

Sift4G

Benign

0.65

T;.;T

Polyphen

0.017

.;.;B

Vest4

0.061

MVP

0.014

ClinPred

0.077

GERP RS

-3.7

Varity_R

0.033

gMVP

0.098

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