6-139373346-TTGCCGC-TTGCCGCTGCCGC

Variant names:

• chr6-139373346-T-TTGCCGC
• rs531316452
• NM_006079.5:c.593_598dupGCGGCA

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM4 BS2_Supporting

The NM_006079.5(CITED2):​c.593_598dupGCGGCA​(p.Ser198_Gly199dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000488 in 1,597,870 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: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: CITED2 NM_006079.5 conservative_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.42
• Publications: 1 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.

• PM4: Nonframeshift variant in NON repetitive region in NM_006079.5.
• BS2: High AC in GnomAd4 at 9 Unknown,AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.593_598dupGCGGCA	p.Ser198_Gly199dup	conservative_inframe_insertion	Exon 2 of 2	NP_006070.2
	CITED2	NM_001168389.3		c.608_613dupGCGGCA	p.Ser203_Gly204dup	conservative_inframe_insertion	Exon 2 of 2	NP_001161861.2	A0A0A0MTM3
	CITED2	NM_001168388.3		c.593_598dupGCGGCA	p.Ser198_Gly199dup	conservative_inframe_insertion	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.593_598dupGCGGCA	p.Ser198_Gly199dup	conservative_inframe_insertion	Exon 2 of 2	ENSP00000356623.2	Q99967-1
	CITED2	ENST00000537332.2	TSL:3	c.608_613dupGCGGCA	p.Ser203_Gly204dup	conservative_inframe_insertion	Exon 2 of 2	ENSP00000444198.2	A0A0A0MTM3
	CITED2	ENST00000536159.2	TSL:3	c.593_598dupGCGGCA	p.Ser198_Gly199dup	conservative_inframe_insertion	Exon 2 of 2	ENSP00000442831.1	Q99967-1

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000588 AC: 13 AN: 221142 AF XY: 0.0000730

Gnomad AFR exome AF: 0.0000853

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000503

Gnomad NFE exome AF: 0.0000824

Gnomad OTH exome AF: 0.000187

GnomAD4 exome AF: 0.0000477 AC: 69 AN: 1445676 Hom.: 0 Cov.: 31 AF XY: 0.0000514 AC XY: 37 AN XY: 719284

African (AFR) AF: 0.0000310 AC: 1 AN: 32210

American (AMR) AF: 0.0000230 AC: 1 AN: 43488

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25774

East Asian (EAS) AF: 0.00 AC: 0 AN: 38516

South Asian (SAS) AF: 0.000153 AC: 13 AN: 84790

European-Finnish (FIN) AF: 0.0000200 AC: 1 AN: 50038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.0000425 AC: 47 AN: 1105648

Other (OTH) AF: 0.000101 AC: 6 AN: 59480

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74426

African (AFR) AF: 0.00 AC: 0 AN: 41562

American (AMR) AF: 0.000196 AC: 3 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67948

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000364 Hom.: 0

Bravo AF: 0.0000416

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.4
Mutation Taster		=64/36	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs531316452; hg19: chr6-139694483; COSMIC: COSV62726159;