Genetic Variant CITED2:p.Gly195del (chr6-139373359-TGCC-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006079.5(CITED2):c.583_585delGGC(p.Gly195del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000278 in 1,439,154 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

CITED2
NM_006079.5 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.99

Publications

0 publications found

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]

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)

CITED2 links:

ENSG00000226571 (HGNC:):

ENSG00000226571 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CITED2	NM_006079.5 link	c.583_585delGGC	p.Gly195del	conservative_inframe_deletion	Exon 2 of 2	ENST00000367651.4	NP_006070.2	Q99967-1D9ZGF1
CITED2	NM_001168389.3 link	c.598_600delGGC	p.Gly200del	conservative_inframe_deletion	Exon 2 of 2		NP_001161861.2	Q99967A0A0A0MTM3
CITED2	NM_001168388.3 link	c.583_585delGGC	p.Gly195del	conservative_inframe_deletion	Exon 2 of 2		NP_001161860.1	Q99967-1D9ZGF1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CITED2	ENST00000367651.4 link	c.583_585delGGC	p.Gly195del	conservative_inframe_deletion	Exon 2 of 2	1	NM_006079.5	ENSP00000356623.2		Q99967-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000140

AC:

AN:

213768

AF XY:

0.0000167

show subpopulations

Gnomad AFR exome

AF:

0.0000921

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000637

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000107

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000278

AC:

AN:

1439154

Hom.:

AF XY:

0.00000559

AC XY:

AN XY:

716016

show subpopulations

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

African (AFR)

AF:

0.0000315

AC:

AN:

31786

American (AMR)

AF:

0.00

AC:

AN:

43022

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25582

East Asian (EAS)

AF:

0.00

AC:

AN:

38144

South Asian (SAS)

AF:

0.00

AC:

AN:

84250

European-Finnish (FIN)

AF:

0.0000206

AC:

AN:

48628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1102796

Other (OTH)

AF:

0.00

AC:

AN:

59238

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.0

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

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chr6-139373359-TGCC-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over