6-139373421-G-A

Variant names:

• chr6-139373421-G-A
• rs982547840
• NM_006079.5:c.524C>T

Variant summary

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

The NM_006079.5(CITED2):​c.524C>T​(p.Thr175Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000725 in 1,379,148 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: 7.3e-7 (0 hom.)
• Consequence: CITED2 NM_006079.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.85

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=0.14840177).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CITED2	NM_006079.5	c.524C>T	p.Thr175Ile	missense_variant	Exon 2 of 2	ENST00000367651.4	NP_006070.2
CITED2	NM_001168389.3	c.539C>T	p.Thr180Ile	missense_variant	Exon 2 of 2		NP_001161861.2
CITED2	NM_001168388.3	c.524C>T	p.Thr175Ile	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.524C>T	p.Thr175Ile	missense_variant	Exon 2 of 2	1	NM_006079.5	ENSP00000356623.2
CITED2	ENST00000537332.2	c.539C>T	p.Thr180Ile	missense_variant	Exon 2 of 2	3		ENSP00000444198.2
CITED2	ENST00000536159.2	c.524C>T	p.Thr175Ile	missense_variant	Exon 2 of 2	3		ENSP00000442831.1
ENSG00000226571	ENST00000650173.1	n.510-55660G>A		intron_variant	Intron 4 of 7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.25e-7 AC: 1 AN: 1379148 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 683872

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: 0.0000138

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

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

not specified Uncertain:1

Sep 27, 2017

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;T;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.58	.;T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;.;L
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.34	N;.;N
REVEL	Benign	0.13
Sift	Benign	0.48	T;.;T
Sift4G	Benign	0.42	T;T;T
Polyphen		0.031	B;.;B
Vest4		0.28
MutPred		0.28		Loss of phosphorylation at T175 (P = 0.0034);.;Loss of phosphorylation at T175 (P = 0.0034);
MVP		0.71
MPC		0.34
ClinPred		0.076	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.079
gMVP		0.61

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: rs982547840; hg19: chr6-139694558;