6-139373337-G-C

Variant names:

• chr6-139373337-G-C
• rs768243056
• NM_006079.5:c.608C>G

Variant summary

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

The NM_006079.5(CITED2):​c.608C>G​(p.Ala203Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,453,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A203V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CITED2 NM_006079.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.50
• 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
• congenital heart disease

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• 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=0.31010604).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006079.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CITED2	NM_006079.5	MANE Select	c.608C>G	p.Ala203Gly	missense	Exon 2 of 2	NP_006070.2
	CITED2	NM_001168389.3		c.623C>G	p.Ala208Gly	missense	Exon 2 of 2	NP_001161861.2	A0A0A0MTM3
	CITED2	NM_001168388.3		c.608C>G	p.Ala203Gly	missense	Exon 2 of 2	NP_001161860.1	Q99967-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CITED2	ENST00000367651.4	TSL:1 MANE Select	c.608C>G	p.Ala203Gly	missense	Exon 2 of 2	ENSP00000356623.2	Q99967-1
	CITED2	ENST00000537332.2	TSL:3	c.623C>G	p.Ala208Gly	missense	Exon 2 of 2	ENSP00000444198.2	A0A0A0MTM3
	CITED2	ENST00000536159.2	TSL:3	c.608C>G	p.Ala203Gly	missense	Exon 2 of 2	ENSP00000442831.1	Q99967-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1453434 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723148

African (AFR) AF: 0.00 AC: 0 AN: 32842

American (AMR) AF: 0.00 AC: 0 AN: 44164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25950

East Asian (EAS) AF: 0.00 AC: 0 AN: 39070

South Asian (SAS) AF: 0.00 AC: 0 AN: 85460

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1108910

Other (OTH) AF: 0.00 AC: 0 AN: 60036

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.070
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.65	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L
PhyloP100		6.5
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.17
Sift	Benign	0.19	T
Sift4G	Benign	0.33	T
Polyphen		0.089	B
Vest4		0.20
MutPred		0.73		Gain of catalytic residue at A203 (P = 0.0571)
MVP		0.37
MPC		0.30
ClinPred		0.72	D
GERP RS		5.4
Varity_R		0.20
gMVP		0.44
Mutation Taster		=84/16	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

dbSNP: rs768243056; hg19: chr6-139694474;