chr2-27326775-A-G

Position:

• chr2-27326775-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001035521.3(GTF3C2):​c.2636T>C​(p.Leu879Pro) 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 benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GTF3C2 NM_001035521.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.08

Genes affected

GTF3C2 (HGNC:4665): (general transcription factor IIIC subunit 2) Contributes to DNA binding activity. Involved in transcription by RNA polymerase III. Located in nucleoplasm. Part of transcription factor TFIIIC complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0798116).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GTF3C2	NM_001035521.3	c.2636T>C	p.Leu879Pro	missense_variant	19/19	ENST00000264720.8	NP_001030598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GTF3C2	ENST00000264720.8	c.2636T>C	p.Leu879Pro	missense_variant	19/19	1	NM_001035521.3	ENSP00000264720	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2023

The c.2636T>C (p.L879P) alteration is located in exon 20 (coding exon 18) of the GTF3C2 gene. This alteration results from a T to C substitution at nucleotide position 2636, causing the leucine (L) at amino acid position 879 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.0042	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.10	T;T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.053
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.56	.;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.080	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.57	N;N
REVEL	Benign	0.27
Sift	Benign	0.14	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.30	B;B
Vest4		0.20
MutPred		0.19		Gain of disorder (P = 0.043);Gain of disorder (P = 0.043);
MVP		0.24
MPC		0.29
ClinPred		0.17	T
GERP RS		4.1
Varity_R		0.15
gMVP		0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs1407054580; hg19: chr2-27549642;