chr6-139373346-T-TTGCCGC

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 AD,Unknown 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;