2-196766634-C-G

Variant names:

• chr2-196766634-C-G
• NM_012086.5:c.2469G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_012086.5(GTF3C3):​c.2469G>C​(p.Gln823His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GTF3C3 NM_012086.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.01
• Publications: 0 publications found

Genes affected

GTF3C3 (HGNC:4666): (general transcription factor IIIC subunit 3) The protein encoded by this gene is part of the TFIIIC2 complex, which binds to the promoters of small nuclear and cytoplasmic RNA genes in order to recruit RNA polymerase III. The TFIIIC2 complex is composed of six subunits. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

GTF3C3 Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.794

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012086.5. 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
	GTF3C3	NM_012086.5	MANE Select	c.2469G>C	p.Gln823His	missense	Exon 17 of 18	NP_036218.1	Q9Y5Q9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GTF3C3	ENST00000263956.8	TSL:1 MANE Select	c.2469G>C	p.Gln823His	missense	Exon 17 of 18	ENSP00000263956.3	Q9Y5Q9-1
	GTF3C3	ENST00000929329.1		c.2496G>C	p.Gln832His	missense	Exon 17 of 18	ENSP00000599388.1
	GTF3C3	ENST00000929328.1		c.2493G>C	p.Gln831His	missense	Exon 18 of 19	ENSP00000599387.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Chromosome 2q32-q33 deletion syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	5.3
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.37	N
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.094	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.9	L
PhyloP100		-1.0
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.54		Gain of methylation at R819 (P = 0.0866)
MVP		0.75
MPC		1.1
ClinPred		1.0	D
GERP RS		-5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.76
Mutation Taster		=53/47	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

hg19: chr2-197631358;