Genetic Variant C12orf57:c.-256C>T (chr12-6943866-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001301834.1(C12orf57):c.-16+204C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0038 in 934,242 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0055 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0035 ( 4 hom. )

Consequence

C12orf57
NM_001301834.1 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:2

Conservation

PhyloP100: 0.538

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:

RNU7-1 (HGNC:34033): (RNA, U7 small nuclear 1) Implicated in Aicardi-Goutieres syndrome. [provided by Alliance of Genome Resources, Apr 2022]

RNU7-1 links:

ENSG00000272173 (HGNC:):

ENSG00000272173 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 12-6943866-C-T is Benign according to our data. Variant chr12-6943866-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1202613.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00551 (839/152298) while in subpopulation AFR AF= 0.0128 (532/41570). AF 95% confidence interval is 0.0119. There are 5 homozygotes in gnomad4. There are 392 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C12orf57	NM_138425.4 link	c.-256C>T		upstream_gene_variant		ENST00000229281.6	NP_612434.1	Q99622

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C12orf57	ENST00000229281.6 link	c.-256C>T		upstream_gene_variant		1	NM_138425.4	ENSP00000229281.5		Q99622

Frequencies

GnomAD3 genomes

AF:

0.00545

AC:

830

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0126

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00323

Gnomad OTH

AF:

0.00478

GnomAD4 exome

AF:

0.00347

AC:

2711

AN:

781944

Hom.:

Cov.:

AF XY:

0.00335

AC XY:

1313

AN XY:

391962

show subpopulations

Gnomad4 AFR exome

AF:

0.0133

Gnomad4 AMR exome

AF:

0.00272

Gnomad4 ASJ exome

AF:

0.00456

Gnomad4 EAS exome

AF:

0.00253

Gnomad4 SAS exome

AF:

0.000707

Gnomad4 FIN exome

AF:

0.000444

Gnomad4 NFE exome

AF:

0.00355

Gnomad4 OTH exome

AF:

0.00408

GnomAD4 genome

AF:

0.00551

AC:

839

AN:

152298

Hom.:

Cov.:

AF XY:

0.00526

AC XY:

392

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0128

Gnomad4 AMR

AF:

0.00307

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.00174

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00323

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.000160

Hom.:

Bravo

AF:

0.00641

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

C12orf57: BS1, BS2; RNU7-1: BS1, BS2 -

Mar 12, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, BS2, PM3, PS3 -

Apr 07, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aicardi-Goutieres syndrome 9

Pathogenic:1

Aug 16, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

1.2

DANN

Benign

0.70

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.3

Splicing

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