chr12-6945798-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS1

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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K86Q) has been classified 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

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 7.29

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

temtamy syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

C12orf57 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

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

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 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 GnomAdExome4. There are 806 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138425.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
C12orf57	NM_138425.4	MANE Select	c.257A>G	p.Lys86Arg	missense	Exon 3 of 3	NP_612434.1	Q99622
C12orf57	NM_001301834.1		c.257A>G	p.Lys86Arg	missense	Exon 4 of 4	NP_001288763.1	Q99622
C12orf57	NM_001301836.2		c.218A>G	p.Lys73Arg	missense	Exon 3 of 3	NP_001288765.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
C12orf57	ENST00000229281.6	TSL:1 MANE Select	c.257A>G	p.Lys86Arg	missense	Exon 3 of 3	ENSP00000229281.5	Q99622
C12orf57	ENST00000852280.1		c.257A>G	p.Lys86Arg	missense	Exon 5 of 5	ENSP00000522339.1
C12orf57	ENST00000545581.5	TSL:3	c.257A>G	p.Lys86Arg	missense	Exon 4 of 4	ENSP00000440602.1	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

GnomAD2 exomes

AF:

0.000596

AC:

149

AN:

250188

AF XY:

0.000665

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 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

African (AFR)

AF:

0.000179

AC:

AN:

33476

American (AMR)

AF:

0.000358

AC:

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.000441

AC:

AN:

86138

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00133

AC:

1479

AN:

1111896

Other (OTH)

AF:

0.00132

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

197

296

394

493

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000572

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41526

American (AMR)

AF:

0.000196

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00100

AC:

AN:

67998

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00133

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Temtamy syndrome (3)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.19

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.052

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.86

M_CAP

Benign

0.019

MetaRNN

Benign

0.051

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.55

PhyloP100

7.3

PROVEAN

Benign

0.49

REVEL

Uncertain

0.42

Sift

Benign

1.0

Sift4G

Benign

0.48

Polyphen

0.013

Vest4

0.47

MVP

0.82

MPC

0.13

ClinPred

0.040

GERP RS

5.2

Varity_R

0.17

gMVP

0.73

Mutation Taster

=71/29

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over