NM_138425.4:c.62C>G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138425.4(C12orf57):​c.62C>G​(p.Ala21Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,612,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. A21V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: C12orf57 NM_138425.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26399133).

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>G	p.Ala21Gly	missense	Exon 2 of 3	NP_612434.1	Q99622
	C12orf57	NM_001301834.1		c.62C>G	p.Ala21Gly	missense	Exon 3 of 4	NP_001288763.1	Q99622
	C12orf57	NM_001301836.2		c.23C>G	p.Ala8Gly	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>G	p.Ala21Gly	missense	Exon 2 of 3	ENSP00000229281.5	Q99622
	C12orf57	ENST00000852280.1		c.62C>G	p.Ala21Gly	missense	Exon 4 of 5	ENSP00000522339.1
	C12orf57	ENST00000545581.5	TSL:3	c.62C>G	p.Ala21Gly	missense	Exon 3 of 4	ENSP00000440602.1	Q99622

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000241 AC: 6 AN: 248728 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1459850 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726224

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.0000896 AC: 4 AN: 44648

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

East Asian (EAS) AF: 0.0000252 AC: 1 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: 0.00 AC: 0 AN: 1111786

Other (OTH) AF: 0.0000166 AC: 1 AN: 60240

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74384

African (AFR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 68050

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Temtamy syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.27	T
Eigen	Benign	0.032
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.60	N
PhyloP100		4.5
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.32
Sift	Benign	0.34	T
Sift4G	Benign	0.43	T
Polyphen		0.0050	B
Vest4		0.17
MutPred		0.20		Gain of catalytic residue at E22 (P = 0.0032)
MVP		0.84
MPC		0.44
ClinPred		0.72	D
GERP RS		3.7
PromoterAI		0.023	Neutral
Varity_R		0.32
gMVP		0.42
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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;