6-139373337-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BS2_Supporting

The NM_006079.5(CITED2):​c.608C>T​(p.Ala203Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000685 in 1,605,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

CITED2
NM_006079.5 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.50
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.34148476).
BS2
High AC in GnomAdExome4 at 9 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CITED2NM_006079.5 linkc.608C>T p.Ala203Val missense_variant Exon 2 of 2 ENST00000367651.4 NP_006070.2 Q99967-1D9ZGF1
CITED2NM_001168389.3 linkc.623C>T p.Ala208Val missense_variant Exon 2 of 2 NP_001161861.2 Q99967A0A0A0MTM3
CITED2NM_001168388.3 linkc.608C>T p.Ala203Val missense_variant Exon 2 of 2 NP_001161860.1 Q99967-1D9ZGF1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CITED2ENST00000367651.4 linkc.608C>T p.Ala203Val missense_variant Exon 2 of 2 1 NM_006079.5 ENSP00000356623.2 Q99967-1
CITED2ENST00000537332.2 linkc.623C>T p.Ala208Val missense_variant Exon 2 of 2 3 ENSP00000444198.2 A0A0A0MTM3
CITED2ENST00000536159.2 linkc.608C>T p.Ala203Val missense_variant Exon 2 of 2 3 ENSP00000442831.1 Q99967-1
ENSG00000226571ENST00000650173.1 linkn.510-55744G>A intron_variant Intron 4 of 7

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152136
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000216
AC:
5
AN:
231582
Hom.:
0
AF XY:
0.0000156
AC XY:
2
AN XY:
127938
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000601
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000294
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000619
AC:
9
AN:
1453434
Hom.:
0
Cov.:
31
AF XY:
0.00000691
AC XY:
5
AN XY:
723148
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000453
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:
0.00000631
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152136
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000574
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.0000166
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Apr 07, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.608C>T (p.A203V) alteration is located in exon 2 (coding exon 1) of the CITED2 gene. This alteration results from a C to T substitution at nucleotide position 608, causing the alanine (A) at amino acid position 203 to be replaced by a valine (V). 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
0.13
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.33
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.20
T;T;T
Eigen
Benign
0.11
Eigen_PC
Uncertain
0.29
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Benign
0.72
.;T;T
M_CAP
Uncertain
0.22
D
MetaRNN
Benign
0.34
T;T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
1.0
L;.;L
PrimateAI
Pathogenic
0.83
D
PROVEAN
Benign
-0.99
N;.;N
REVEL
Benign
0.13
Sift
Uncertain
0.029
D;.;D
Sift4G
Benign
0.30
T;T;T
Polyphen
0.19
B;.;B
Vest4
0.30
MutPred
0.72
Gain of catalytic residue at A203 (P = 0.0718);.;Gain of catalytic residue at A203 (P = 0.0718);
MVP
0.36
MPC
0.33
ClinPred
0.57
D
GERP RS
5.4
Varity_R
0.31
gMVP
0.54

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs768243056; hg19: chr6-139694474; API