6-139373346-TTGCCGC-T

Variant names:

• chr6-139373346-TTGCCGC-T
• rs531316452
• NM_006079.5:c.593_598delGCGGCA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM4 BP6_Very_Strong BS2

The NM_001168389.3(CITED2):​c.608_613delGCGGCA​(p.Ser203_Gly204del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000507 in 1,597,862 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (0 hom.)
• Consequence: CITED2 NM_001168389.3 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts P:1 B:2
• Conservation: PhyloP100: 2.57
• 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
• ventricular septal defect 2

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000226571 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001168389.3.
• BP6: Variant 6-139373346-TTGCCGC-T is Benign according to our data. Variant chr6-139373346-TTGCCGC-T is described in ClinVar as [Likely_benign]. Clinvar id is 6723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 213 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CITED2	NM_006079.5	c.593_598delGCGGCA	p.Ser198_Gly199del	disruptive_inframe_deletion	Exon 2 of 2	ENST00000367651.4	NP_006070.2
CITED2	NM_001168389.3	c.608_613delGCGGCA	p.Ser203_Gly204del	disruptive_inframe_deletion	Exon 2 of 2		NP_001161861.2
CITED2	NM_001168388.3	c.593_598delGCGGCA	p.Ser198_Gly199del	disruptive_inframe_deletion	Exon 2 of 2		NP_001161860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CITED2	ENST00000367651.4	c.593_598delGCGGCA	p.Ser198_Gly199del	disruptive_inframe_deletion	Exon 2 of 2	1	NM_006079.5	ENSP00000356623.2

Frequencies

GnomAD3 genomes AF: 0.00140 AC: 213 AN: 152082 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00311

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000407 AC: 90 AN: 221142 AF XY: 0.000381

Gnomad AFR exome AF: 0.00350

Gnomad AMR exome AF: 0.000217

Gnomad ASJ exome AF: 0.000213

Gnomad EAS exome AF: 0.0000614

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000278

Gnomad OTH exome AF: 0.00112

GnomAD4 exome AF: 0.000413 AC: 597 AN: 1445668 Hom.: 0 AF XY: 0.000412 AC XY: 296 AN XY: 719280

African (AFR) AF: 0.00289 AC: 93 AN: 32210

American (AMR) AF: 0.000644 AC: 28 AN: 43488

Ashkenazi Jewish (ASJ) AF: 0.000116 AC: 3 AN: 25774

East Asian (EAS) AF: 0.000182 AC: 7 AN: 38516

South Asian (SAS) AF: 0.000165 AC: 14 AN: 84790

European-Finnish (FIN) AF: 0.0000200 AC: 1 AN: 50036

Middle Eastern (MID) AF: 0.000698 AC: 4 AN: 5732

European-Non Finnish (NFE) AF: 0.000357 AC: 395 AN: 1105642

Other (OTH) AF: 0.000874 AC: 52 AN: 59480

GnomAD4 genome AF: 0.00140 AC: 213 AN: 152194 Hom.: 1 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74426

African (AFR) AF: 0.00310 AC: 129 AN: 41562

American (AMR) AF: 0.00281 AC: 43 AN: 15282

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

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 67948

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000291 Hom.: 0

Bravo AF: 0.00176

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Atrial septal defect 8 Pathogenic:1

Dec 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Ventricular septal defect 2 Benign:1

Jan 18, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.6
Mutation Taster		=9/191	disease causing

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: COSV62726738;