dbSNP rs139938808: C12orf57:p.Ala29Val (chr12-6944509-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_138425.4(C12orf57):c.86C>T(p.Ala29Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000399 in 1,613,384 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00022 ( 2 hom. )

Consequence

C12orf57
NM_138425.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 3.43

Publications

4 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:

ENSG00000272173 (HGNC:):

ENSG00000272173 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009012699).

BP6

Variant 12-6944509-C-T is Benign according to our data. Variant chr12-6944509-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210550.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00215 (327/152366) while in subpopulation AFR AF = 0.00673 (280/41592). AF 95% confidence interval is 0.00608. There are 1 homozygotes in GnomAd4. There are 142 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

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.86C>T	p.Ala29Val	missense	Exon 2 of 3	NP_612434.1	Q99622
C12orf57	NM_001301834.1		c.86C>T	p.Ala29Val	missense	Exon 3 of 4	NP_001288763.1	Q99622
C12orf57	NM_001301836.2		c.47C>T	p.Ala16Val	missense	Exon 2 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.86C>T	p.Ala29Val	missense	Exon 2 of 3	ENSP00000229281.5	Q99622
C12orf57	ENST00000852280.1		c.86C>T	p.Ala29Val	missense	Exon 4 of 5	ENSP00000522339.1
C12orf57	ENST00000545581.5	TSL:3	c.86C>T	p.Ala29Val	missense	Exon 3 of 4	ENSP00000440602.1	Q99622

Frequencies

GnomAD3 genomes

AF:

0.00215

AC:

327

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00675

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00223

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:

0.000147

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000511

AC:

128

AN:

250504

AF XY:

0.000376

show subpopulations

Gnomad AFR exome

AF:

0.00637

Gnomad AMR exome

AF:

0.000492

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000530

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000216

AC:

316

AN:

1461018

Hom.:

Cov.:

AF XY:

0.000191

AC XY:

139

AN XY:

726814

show subpopulations

African (AFR)

AF:

0.00562

AC:

188

AN:

33448

American (AMR)

AF:

0.000559

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86210

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53300

Middle Eastern (MID)

AF:

0.000953

AC:

AN:

5246

European-Non Finnish (NFE)

AF:

0.0000549

AC:

AN:

1111964

Other (OTH)

AF:

0.000580

AC:

AN:

60312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.00215

AC:

327

AN:

152366

Hom.:

Cov.:

AF XY:

0.00191

AC XY:

142

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.00673

AC:

280

AN:

41592

American (AMR)

AF:

0.00222

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68036

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.000783

Hom.:

Bravo

AF:

0.00247

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000610

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

C12orf57-related disorder (1)

not specified (1)

Temtamy syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.086

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.75

M_CAP

Benign

0.026

MetaRNN

Benign

0.0090

MetaSVM

Benign

-0.66

MutationAssessor

Benign

1.1

PhyloP100

3.4

PROVEAN

Benign

-1.2

REVEL

Benign

0.27

Sift

Benign

0.31

Sift4G

Benign

0.51

Polyphen

0.0070

Vest4

0.10

MVP

0.80

MPC

0.15

ClinPred

0.048

GERP RS

3.7

PromoterAI

0.014

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.38

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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