Genetic Variant C12orf56:p.Gly247Glu (chr12-64318729-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_001170633.2(C12orf56):c.740G>A(p.Gly247Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000294 in 1,536,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00030 ( 0 hom. )

Consequence

C12orf56
NM_001170633.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.161

Variant links:

Genes affected

C12orf56 (HGNC:26967): (chromosome 12 open reading frame 56)

C12orf56 links:

ENSG00000243024 (HGNC:):

ENSG00000243024 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=0.02559191).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C12orf56	NM_001170633.2 link	c.740G>A	p.Gly247Glu	missense_variant	Exon 4 of 13	ENST00000543942.7	NP_001164104.1	Q8IXR9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
C12orf56	ENST00000543942.7 link	c.740G>A	p.Gly247Glu	missense_variant	Exon 4 of 13	5	NM_001170633.2	ENSP00000446101.2	Q8IXR9-1
C12orf56	ENST00000333722.9 link	c.488+12231G>A		intron_variant	Intron 3 of 10	1		ENSP00000329698.5	Q8IXR9-2
C12orf56	ENST00000543259.1 link	c.450-5977G>A		intron_variant	Intron 3 of 4	4		ENSP00000443341.1	H0YGI1
ENSG00000243024	ENST00000535684.6 link	n.324-70304C>T		intron_variant	Intron 2 of 4	2

Frequencies

GnomAD3 genomes

AF:

0.000198

AC:

AN:

151872

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000368

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000201

AC:

AN:

139482

Hom.:

AF XY:

0.000227

AC XY:

AN XY:

74794

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.000556

Gnomad NFE exome

AF:

0.000447

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000305

AC:

422

AN:

1384938

Hom.:

Cov.:

AF XY:

0.000303

AC XY:

207

AN XY:

683396

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000840

Gnomad4 ASJ exome

AF:

0.0000397

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000314

Gnomad4 NFE exome

AF:

0.000359

Gnomad4 OTH exome

AF:

0.000345

GnomAD4 genome

AF:

0.000197

AC:

AN:

151990

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000368

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.000256

Hom.:

Bravo

AF:

0.000174

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000497

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.740G>A (p.G247E) alteration is located in exon 4 (coding exon 4) of the C12orf56 gene. This alteration results from a G to A substitution at nucleotide position 740, causing the glycine (G) at amino acid position 247 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

0.088

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.40

DEOGEN2

Benign

0.0046

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.47

M_CAP

Benign

0.0010

MetaRNN

Benign

0.026

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

PROVEAN

Benign

0.35

REVEL

Benign

0.036

Sift

Benign

0.53

Sift4G

Benign

0.68

Vest4

0.10

MutPred

0.11

Loss of sheet (P = 0.0315);

MVP

0.030

ClinPred

0.014

GERP RS

0.18

Varity_R

0.081

gMVP

0.24

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