18-22171919-G-C

Variant names:

• chr18-22171919-G-C
• rs911752926
• NM_005257.6:c.775G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005257.6(GATA6):​c.775G>C​(p.Val259Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000195 in 1,026,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V259I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: GATA6 NM_005257.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.617
• Publications: 2 publications found

Genes affected

GATA6 (HGNC:4174): (GATA binding protein 6) This gene is a member of a small family of zinc finger transcription factors that play an important role in the regulation of cellular differentiation and organogenesis during vertebrate development. This gene is expressed during early embryogenesis and localizes to endo- and mesodermally derived cells during later embryogenesis and thereby plays an important role in gut, lung, and heart development. Mutations in this gene are associated with several congenital defects. [provided by RefSeq, Mar 2012]

GATA6 Gene-Disease associations (from GenCC):

• atrial septal defect 9

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: G2P, Ambry Genetics
• atrioventricular septal defect 5

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• GATA6-related congenital heart disease with or without pancreatic agenesis or neonatal diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• pancreatic hypoplasia-diabetes-congenital heart disease syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• metabolic syndrome

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• neonatal diabetes mellitus

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tetralogy of fallot

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• conotruncal heart malformations

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34684706).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005257.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATA6	NM_005257.6	MANE Select	c.775G>C	p.Val259Leu	missense	Exon 2 of 7	NP_005248.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATA6	ENST00000269216.10	TSL:1 MANE Select	c.775G>C	p.Val259Leu	missense	Exon 2 of 7	ENSP00000269216.3
	GATA6	ENST00000581694.1	TSL:1	c.775G>C	p.Val259Leu	missense	Exon 1 of 6	ENSP00000462313.1
	GATA6	ENST00000853536.1		c.775G>C	p.Val259Leu	missense	Exon 2 of 8	ENSP00000523595.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000195 AC: 2 AN: 1026456 Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 2 AN XY: 483796

African (AFR) AF: 0.00 AC: 0 AN: 20876

American (AMR) AF: 0.000151 AC: 1 AN: 6626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11730

East Asian (EAS) AF: 0.00 AC: 0 AN: 21128

South Asian (SAS) AF: 0.00 AC: 0 AN: 19086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2600

European-Non Finnish (NFE) AF: 0.00000113 AC: 1 AN: 885568

Other (OTH) AF: 0.00 AC: 0 AN: 39562

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.82	D
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.51	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	0.041	D
MutationAssessor	Benign	1.5	L
PhyloP100		0.62
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.27
Sift	Benign	0.14	T
Sift4G	Benign	0.59	T
Polyphen		0.019	B
Vest4		0.090
MutPred		0.24		Gain of catalytic residue at S254 (P = 0.1532)
MVP		0.94
ClinPred		0.091	T
GERP RS		0.28
Varity_R		0.12
gMVP		0.32
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs911752926; hg19: chr18-19751880;