chr6-139373314-C-T

Variant names:

• chr6-139373314-C-T
• NM_006079.5:c.631G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006079.5(CITED2):​c.631G>A​(p.Ala211Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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: 0.0000014 (0 hom.)
• Consequence: CITED2 NM_006079.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.39
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28374797).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CITED2	NM_006079.5	c.631G>A	p.Ala211Thr	missense_variant	Exon 2 of 2	ENST00000367651.4	NP_006070.2
CITED2	NM_001168389.3	c.646G>A	p.Ala216Thr	missense_variant	Exon 2 of 2		NP_001161861.2
CITED2	NM_001168388.3	c.631G>A	p.Ala211Thr	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.631G>A	p.Ala211Thr	missense_variant	Exon 2 of 2	1	NM_006079.5	ENSP00000356623.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460930 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726754

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111890

Other (OTH) AF: 0.00 AC: 0 AN: 60372

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

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

Dec 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.631G>A (p.A211T) 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 631, causing the alanine (A) at amino acid position 211 to be replaced by a threonine (T). 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	0.25
BayesDel_addAF	Benign	-0.0081	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.028
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.83	.;T;T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;.;L
PhyloP100		1.4
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.0	N;.;N
REVEL	Benign	0.17
Sift	Uncertain	0.011	D;.;D
Sift4G	Benign	0.16	T;T;T
Polyphen		0.17	B;.;B
Vest4		0.42
MutPred		0.74		Gain of glycosylation at A211 (P = 0.0012);.;Gain of glycosylation at A211 (P = 0.0012);
MVP		0.45
MPC		1.0
ClinPred		0.96	D
GERP RS		4.4
Varity_R		0.36
gMVP		0.54
Mutation Taster		=73/27	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: chr6-139694451;