2-75689057-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003203.5(GCFC2):c.1508G>A(p.Arg503Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000593 in 1,584,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: GCFC2 NM_003203.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.03

Genes affected

GCFC2 (HGNC:1317): (GC-rich sequence DNA-binding factor 2) The first mRNA transcript isolated for this gene was part of an artificial chimera derived from two distinct gene transcripts and a primer used in the cloning process (see Genbank accession M29204). A positively charged amino terminus present only in the chimera was determined to bind GC-rich DNA, thus mistakenly thought to identify a transcription factor gene. [provided by RefSeq, Jul 2008]

LOC124906025 (HGNC:):

MRPL19 (HGNC:14052): (mitochondrial ribosomal protein L19) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 39S subunit protein. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.748

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCFC2	NM_003203.5	c.1508G>A	p.Arg503Gln	missense_variant	10/17	ENST00000321027.8
LOC124906025	XR_007087113.1	n.7538-1577C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCFC2	ENST00000321027.8	c.1508G>A	p.Arg503Gln	missense_variant	10/17	1	NM_003203.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000659 AC: 16 AN: 242624 Hom.: 0 AF XY: 0.0000762 AC XY: 10 AN XY: 131302

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000308

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.0000901

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000559 AC: 80 AN: 1432316 Hom.: 0 Cov.: 26 AF XY: 0.0000588 AC XY: 42 AN XY: 713726

Gnomad4 AFR exome AF: 0.0000308

Gnomad4 AMR exome AF: 0.0000941

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000715

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000750

Gnomad4 NFE exome AF: 0.0000348

Gnomad4 OTH exome AF: 0.0000842

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74388

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000115 Hom.: 0

Bravo AF: 0.0000982

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000659 AC: 8

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

Aug 02, 2021

The c.1508G>A (p.R503Q) alteration is located in exon 10 (coding exon 10) of the GCFC2 gene. This alteration results from a G to A substitution at nucleotide position 1508, causing the arginine (R) at amino acid position 503 to be replaced by a glutamine (Q). 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	0.20
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.090
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.29	T;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Pathogenic	3.4	M;.
MutationTaster	Benign	0.83	D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.020	D;D
Polyphen		1.0	D;.
Vest4		0.91
MVP		0.69
MPC		0.51
ClinPred		0.79	D
GERP RS		2.7
Varity_R		0.28
gMVP		0.80

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

LitVar

Other links and lift over

dbSNP: rs374515599; hg19: chr2-75916183;