12-6944485-C-T

Variant names:

• chr12-6944485-C-T
• rs146024802
• NM_138425.4:c.62C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_138425.4(C12orf57):​c.62C>T​(p.Ala21Val) variant causes a missense change. The variant allele was found at a frequency of 0.000548 in 1,612,100 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A21T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00059 (1 hom.)
• Consequence: C12orf57 NM_138425.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 4.52
• Publications: 5 publications found

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

ENSG00000272173 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25009143).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C12orf57	NM_138425.4	MANE Select	c.62C>T	p.Ala21Val	missense	Exon 2 of 3	NP_612434.1	Q99622
	C12orf57	NM_001301834.1		c.62C>T	p.Ala21Val	missense	Exon 3 of 4	NP_001288763.1	Q99622
	C12orf57	NM_001301836.2		c.23C>T	p.Ala8Val	missense	Exon 2 of 3	NP_001288765.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C12orf57	ENST00000229281.6	TSL:1 MANE Select	c.62C>T	p.Ala21Val	missense	Exon 2 of 3	ENSP00000229281.5	Q99622
	C12orf57	ENST00000852280.1		c.62C>T	p.Ala21Val	missense	Exon 4 of 5	ENSP00000522339.1
	C12orf57	ENST00000545581.5	TSL:3	c.62C>T	p.Ala21Val	missense	Exon 3 of 4	ENSP00000440602.1	Q99622

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000213 AC: 53 AN: 248728 AF XY: 0.000208

Gnomad AFR exome AF: 0.0000626

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000410

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000593 AC: 865 AN: 1459850 Hom.: 1 Cov.: 32 AF XY: 0.000584 AC XY: 424 AN XY: 726224

African (AFR) AF: 0.0000898 AC: 3 AN: 33418

American (AMR) AF: 0.000157 AC: 7 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4736

European-Non Finnish (NFE) AF: 0.000747 AC: 831 AN: 1111786

Other (OTH) AF: 0.000398 AC: 24 AN: 60240

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74384

African (AFR) AF: 0.0000241 AC: 1 AN: 41450

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68050

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000318 Hom.: 0

Bravo AF: 0.000181

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000273

EpiControl AF: 0.000534

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Temtamy syndrome (2)
-	1	-	C12orf57-related disorder (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.5
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.37
Sift	Benign	0.24	T
Sift4G	Benign	0.12	T
Polyphen		0.90	P
Vest4		0.48
MVP		0.87
MPC		0.53
ClinPred		0.35	T
GERP RS		3.7
PromoterAI		-0.035	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.52
Mutation Taster		=69/31	polymorphism

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

Other links and lift over

dbSNP: rs146024802; hg19: chr12-7053648;