rs139068225

Positions:

chr12-6945798-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_138425.4(C12orf57):c.257A>G(p.Lys86Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,613,780 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00057 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 1 hom. )

Consequence

C12orf57
NM_138425.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.29

Variant links:

Genes affected

C12orf57 (HGNC:29521): (chromosome 12 open reading frame 57) This gene is ubiquitously expressed in human tissues. It is required for development of the human corpus callosum. Mutations in this gene are associated with Temtamy syndrome (TEMTYS). Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2014]

C12orf57 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.051499456).

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00112 (1634/1461550) while in subpopulation NFE AF= 0.00133 (1479/1111896). AF 95% confidence interval is 0.00127. There are 1 homozygotes in gnomad4_exome. There are 806 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C12orf57	NM_138425.4 link	c.257A>G	p.Lys86Arg	missense_variant	3/3	ENST00000229281.6	NP_612434.1	Q99622

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C12orf57	ENST00000229281.6 link	c.257A>G	p.Lys86Arg	missense_variant	3/3	1	NM_138425.4	ENSP00000229281.5		Q99622

Frequencies

GnomAD3 genomes

AF:

0.000572

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00100

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000596

AC:

149

AN:

250188

Hom.:

AF XY:

0.000665

AC XY:

AN XY:

135274

show subpopulations

Gnomad AFR exome

AF:

0.000371

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000525

Gnomad FIN exome

AF:

0.000327

Gnomad NFE exome

AF:

0.000919

Gnomad OTH exome

AF:

0.000981

GnomAD4 exome

AF:

0.00112

AC:

1634

AN:

1461550

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

806

AN XY:

727032

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000441

Gnomad4 FIN exome

AF:

0.000112

Gnomad4 NFE exome

AF:

0.00133

Gnomad4 OTH exome

AF:

0.00132

GnomAD4 genome

AF:

0.000572

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00100

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00148

Hom.:

Bravo

AF:

0.000601

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000502

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.00125

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Temtamy syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Mar 18, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 18, 2022	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 86 of the C12orf57 protein (p.Lys86Arg). This variant is present in population databases (rs139068225, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with C12orf57-related conditions. ClinVar contains an entry for this variant (Variation ID: 210548). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 24, 2015

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.19

T;T;T;T

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.052

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.86

.;D;D;D

M_CAP

Benign

0.019

MetaRNN

Benign

0.051

T;T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.55

N;.;N;.

PROVEAN

Benign

0.49

N;N;N;.

REVEL

Uncertain

0.42

Sift

Benign

1.0

T;D;T;.

Sift4G

Benign

0.48

T;T;T;T

Polyphen

0.013

B;.;B;.

Vest4

0.47, 0.42, 0.43

MVP

0.82

MPC

0.13

ClinPred

0.040

GERP RS

5.2

Varity_R

0.17

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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