6-139373371-T-C

Position:

• chr6-139373371-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006079.5(CITED2):​c.574A>G​(p.Ser192Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000925 in 1,588,050 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (22 hom.)
• Consequence: CITED2 NM_006079.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.338

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0075461864).
• BP6: Variant 6-139373371-T-C is Benign according to our data. Variant chr6-139373371-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 668342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000804 (1155/1436108) while in subpopulation AMR AF= 0.0189 (799/42316). AF 95% confidence interval is 0.0178. There are 22 homozygotes in gnomad4_exome. There are 533 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 314 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CITED2	NM_006079.5	c.574A>G	p.Ser192Gly	missense_variant	2/2	ENST00000367651.4	NP_006070.2
CITED2	NM_001168389.3	c.589A>G	p.Ser197Gly	missense_variant	2/2		NP_001161861.2
CITED2	NM_001168388.3	c.574A>G	p.Ser192Gly	missense_variant	2/2		NP_001161860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CITED2	ENST00000367651.4	c.574A>G	p.Ser192Gly	missense_variant	2/2	1	NM_006079.5	ENSP00000356623	P1
	ENST00000650173.1	n.510-55710T>C		intron_variant, non_coding_transcript_variant
CITED2	ENST00000537332.2	c.589A>G	p.Ser197Gly	missense_variant	2/2	3		ENSP00000444198
CITED2	ENST00000536159.2	c.574A>G	p.Ser192Gly	missense_variant	2/2	3		ENSP00000442831	P1

Frequencies

GnomAD3 genomes AF: 0.00207 AC: 314 AN: 151834 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000774

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0157

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00214

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000853

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00319 AC: 687 AN: 215250 Hom.: 16 AF XY: 0.00268 AC XY: 321 AN XY: 119966

Gnomad AFR exome AF: 0.000272

Gnomad AMR exome AF: 0.0189

Gnomad ASJ exome AF: 0.00120

Gnomad EAS exome AF: 0.00193

Gnomad SAS exome AF: 0.000246

Gnomad FIN exome AF: 0.000818

Gnomad NFE exome AF: 0.000231

Gnomad OTH exome AF: 0.00233

GnomAD4 exome AF: 0.000804 AC: 1155 AN: 1436108 Hom.: 22 Cov.: 31 AF XY: 0.000746 AC XY: 533 AN XY: 714526

Gnomad4 AFR exome AF: 0.000350

Gnomad4 AMR exome AF: 0.0189

Gnomad4 ASJ exome AF: 0.00153

Gnomad4 EAS exome AF: 0.00181

Gnomad4 SAS exome AF: 0.000179

Gnomad4 FIN exome AF: 0.000545

Gnomad4 NFE exome AF: 0.000110

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.00207 AC: 314 AN: 151942 Hom.: 5 Cov.: 32 AF XY: 0.00230 AC XY: 171 AN XY: 74262

Gnomad4 AFR AF: 0.000772

Gnomad4 AMR AF: 0.0157

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00215

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000853

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00139 Hom.: 0

Bravo AF: 0.00296

ExAC AF: 0.000871 AC: 101

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CITED2: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	3.5
DANN	Benign	0.69
DEOGEN2	Benign	0.13	T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0056	N
LIST_S2	Benign	0.29	.;T;T
MetaRNN	Benign	0.0075	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;.;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	0.71	N;.;N
REVEL	Uncertain	0.36
Sift	Benign	1.0	T;.;T
Sift4G	Benign	0.42	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.65
MVP		0.99
MPC		0.28
ClinPred		0.012	T
GERP RS		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.030
gMVP		0.34

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

LitVar

Other links and lift over

dbSNP: rs563655306; hg19: chr6-139694508;