Genetic Variant C2orf81:p.Ala49Thr (chr2-74416115-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001316764.3(C2orf81):c.145G>A(p.Ala49Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000408 in 1,536,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00043 ( 0 hom. )

Consequence

C2orf81
NM_001316764.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0370

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13326466).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C2orf81	NM_001316764.3 link	c.145G>A	p.Ala49Thr	missense_variant	Exon 2 of 3	ENST00000684111.1	NP_001303693.1	A0A804HJ35
C2orf81	NM_001145054.2 link	c.154G>A	p.Ala52Thr	missense_variant	Exon 2 of 4		NP_001138526.1	G3XAA6
C2orf81	NM_001316766.2 link	c.-224G>A		5_prime_UTR_variant	Exon 2 of 2		NP_001303695.1	A0A1W2PQG2
C2orf81	NM_001316765.2 link	c.102+43G>A		intron_variant	Intron 2 of 2		NP_001303694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
C2orf81	ENST00000684111.1 link	c.145G>A	p.Ala49Thr	missense_variant	Exon 2 of 3		NM_001316764.3	ENSP00000507340.1	A0A804HJ35
ENSG00000159239	ENST00000517883.2 link	n.-224G>A		non_coding_transcript_exon_variant	Exon 2 of 5	5		ENSP00000431103.2	E5RJQ4
ENSG00000159239	ENST00000517883.2 link	n.-224G>A		5_prime_UTR_variant	Exon 2 of 5	5		ENSP00000431103.2	E5RJQ4

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000964

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.000353

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000205

AC:

AN:

155780

Hom.:

AF XY:

0.000218

AC XY:

AN XY:

82656

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000614

Gnomad NFE exome

AF:

0.000480

Gnomad OTH exome

AF:

0.000228

GnomAD4 exome

AF:

0.000430

AC:

595

AN:

1384118

Hom.:

Cov.:

AF XY:

0.000378

AC XY:

258

AN XY:

682432

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000402

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000636

Gnomad4 NFE exome

AF:

0.000538

Gnomad4 OTH exome

AF:

0.000263

GnomAD4 genome

AF:

0.000210

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.0000964

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000360

Hom.:

Bravo

AF:

0.000204

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000156

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.154G>A (p.A52T) alteration is located in exon 2 (coding exon 2) of the C2orf81 gene. This alteration results from a G to A substitution at nucleotide position 154, causing the alanine (A) at amino acid position 52 to be replaced by a threonine (T). 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

-0.34

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.94

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.15

FATHMM_MKL

Benign

0.071

LIST_S2

Benign

0.67

T;T;T;T

M_CAP

Benign

0.0054

MetaRNN

Benign

0.13

T;T;T;T

MetaSVM

Benign

-0.93

PROVEAN

Benign

-1.8

.;N;.;.

REVEL

Benign

0.11

Sift

Uncertain

0.017

.;D;.;.

Sift4G

Uncertain

0.036

D;D;.;.

Polyphen

0.99

.;D;.;.

Vest4

0.24

MVP

0.072

ClinPred

0.16

GERP RS

4.6

Varity_R

0.064

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