6-139373383-C-T

Variant names:

• chr6-139373383-C-T
• rs963947198
• NM_006079.5:c.562G>A

Variant summary

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

The NM_006079.5(CITED2):​c.562G>A​(p.Gly188Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000281 in 1,421,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CITED2 NM_006079.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.259

Genes affected

CITED2 (HGNC:1987): (Cbp/p300 interacting transactivator with Glu/Asp rich carboxy-terminal domain 2) The protein encoded by this gene inhibits transactivation of HIF1A-induced genes by competing with binding of hypoxia-inducible factor 1-alpha to p300-CH1. Mutations in this gene are a cause of cardiac septal defects. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, May 2012]

ENSG00000226571 (HGNC:):

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=0.11277273).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CITED2	NM_006079.5	c.562G>A	p.Gly188Ser	missense_variant	Exon 2 of 2	ENST00000367651.4	NP_006070.2
CITED2	NM_001168389.3	c.577G>A	p.Gly193Ser	missense_variant	Exon 2 of 2		NP_001161861.2
CITED2	NM_001168388.3	c.562G>A	p.Gly188Ser	missense_variant	Exon 2 of 2		NP_001161860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CITED2	ENST00000367651.4	c.562G>A	p.Gly188Ser	missense_variant	Exon 2 of 2	1	NM_006079.5	ENSP00000356623.2
CITED2	ENST00000537332.2	c.577G>A	p.Gly193Ser	missense_variant	Exon 2 of 2	3		ENSP00000444198.2
CITED2	ENST00000536159.2	c.562G>A	p.Gly188Ser	missense_variant	Exon 2 of 2	3		ENSP00000442831.1
ENSG00000226571	ENST00000650173.1	n.510-55698C>T		intron_variant	Intron 4 of 7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000281 AC: 4 AN: 1421654 Hom.: 0 Cov.: 31 AF XY: 0.00000283 AC XY: 2 AN XY: 706624

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000366

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.562G>A (p.G188S) alteration is located in exon 2 (coding exon 1) of the CITED2 gene. This alteration results from a G to A substitution at nucleotide position 562, causing the glycine (G) at amino acid position 188 to be replaced by a serine (S). 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	0.073
BayesDel_addAF	Benign	-0.0095	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;T;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.61	.;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;.;L
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.47	N;N;N
REVEL	Benign	0.067
Sift	Benign	0.42	T;T;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.0020	B;.;B
Vest4		0.27
MutPred		0.47		Gain of phosphorylation at G188 (P = 9e-04);.;Gain of phosphorylation at G188 (P = 9e-04);
MVP		0.55
MPC		0.30
ClinPred		0.11	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.069
gMVP		0.48

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: rs963947198; hg19: chr6-139694520;