NM_006079.5:c.663T>G

Variant names:

• chr6-139373282-A-C
• NM_006079.5:c.663T>G

Variant summary

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

The NM_006079.5(CITED2):​c.663T>G​(p.Asp221Glu) 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: CITED2 NM_006079.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.40
• Publications: 0 publications found

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]

CITED2 Gene-Disease associations (from GenCC):

• atrial septal defect 8

  Inheritance: AD Classification: MODERATE Submitted by: Laboratory for Molecular Medicine
• congenital heart defects, multiple types

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• ventricular septal defect 2

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000226571 (HGNC:):

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, 0.81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CITED2	NM_006079.5	c.663T>G	p.Asp221Glu	missense_variant	Exon 2 of 2	ENST00000367651.4	NP_006070.2
CITED2	NM_001168389.3	c.678T>G	p.Asp226Glu	missense_variant	Exon 2 of 2		NP_001161861.2
CITED2	NM_001168388.3	c.663T>G	p.Asp221Glu	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.663T>G	p.Asp221Glu	missense_variant	Exon 2 of 2	1	NM_006079.5	ENSP00000356623.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Jan 02, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.663T>G (p.D221E) alteration is located in exon 2 (coding exon 1) of the CITED2 gene. This alteration results from a T to G substitution at nucleotide position 663, causing the aspartic acid (D) at amino acid position 221 to be replaced by a glutamic acid (E). 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	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;T;T;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.65	.;T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.49	N;.;N;.
PhyloP100		2.4
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.3	D;.;D;.
REVEL	Uncertain	0.52
Sift	Benign	0.10	T;.;T;.
Sift4G	Benign	0.11	T;T;T;T
Polyphen		0.91	P;.;P;.
Vest4		0.91
MutPred		0.66		Gain of catalytic residue at D221 (P = 0.1214);.;Gain of catalytic residue at D221 (P = 0.1214);.;
MVP		0.90
MPC		0.54
ClinPred		0.94	D
GERP RS		3.0
Varity_R		0.52
gMVP		0.93
Mutation Taster		=55/45	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: chr6-139694419;