6-139373356-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006079.5(CITED2):c.589G>C(p.Gly197Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,439,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CITED2 NM_006079.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.475

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40571514).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CITED2	NM_006079.5	c.589G>C	p.Gly197Arg	missense_variant	2/2	ENST00000367651.4
CITED2	NM_001168389.3	c.604G>C	p.Gly202Arg	missense_variant	2/2
CITED2	NM_001168388.3	c.589G>C	p.Gly197Arg	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CITED2	ENST00000367651.4	c.589G>C	p.Gly197Arg	missense_variant	2/2	1	NM_006079.5	P1
	ENST00000650173.1	n.510-55725C>G		intron_variant, non_coding_transcript_variant
CITED2	ENST00000537332.2	c.604G>C	p.Gly202Arg	missense_variant	2/2	3
CITED2	ENST00000536159.2	c.589G>C	p.Gly197Arg	missense_variant	2/2	3		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1439652 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 716244

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: 9.06e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 15, 2023

The c.589G>C (p.G197R) alteration is located in exon 2 (coding exon 1) of the CITED2 gene. This alteration results from a G to C substitution at nucleotide position 589, causing the glycine (G) at amino acid position 197 to be replaced by an arginine (R). 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	Uncertain	0.39
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	13
Dann	Uncertain	0.98
DEOGEN2	Benign	0.13	T;T;T
Eigen	Benign	-0.074
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.080	N
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;.;L
MutationTaster	Benign	0.84	N;N;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.58	N;.;N
REVEL	Uncertain	0.34
Sift	Benign	0.17	T;.;T
Sift4G	Benign	0.51	T;T;T
Polyphen		0.99	D;.;D
Vest4		0.31
MutPred		0.65		Gain of MoRF binding (P = 0.0532);.;Gain of MoRF binding (P = 0.0532);
MVP		0.71
MPC		0.37
ClinPred		0.43	T
GERP RS		3.1
Varity_R		0.18
gMVP		0.20

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-139694493;