18-22171995-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005257.6(GATA6):c.851C>G(p.Ala284Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00558 in 1,228,436 control chromosomes in the GnomAD database, including 321 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A284E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.027 ( 187 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 134 hom. )

Consequence

GATA6
NM_005257.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.36

Publications

3 publications found

Variant links:

COSMIC-nc: COSV52528320

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

GATA6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0035056472).

BP6

Variant 18-22171995-C-G is Benign according to our data. Variant chr18-22171995-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0906 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATA6	NM_005257.6 link	c.851C>G	p.Ala284Gly	missense_variant	Exon 2 of 7	ENST00000269216.10	NP_005248.2
GATA6	XM_047437483.1 link	c.851C>G	p.Ala284Gly	missense_variant	Exon 2 of 7		XP_047293439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATA6	ENST00000269216.10 link	c.851C>G	p.Ala284Gly	missense_variant	Exon 2 of 7	1	NM_005257.6	ENSP00000269216.3
GATA6	ENST00000581694.1 link	c.851C>G	p.Ala284Gly	missense_variant	Exon 1 of 6	1		ENSP00000462313.1

Frequencies

GnomAD3 genomes

AF:

0.0270

AC:

4085

AN:

151018

Hom.:

189

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0932

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0113

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000355

Gnomad OTH

AF:

0.0188

GnomAD2 exomes

AF:

0.00

AC:

AN:

324

AF XY:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00257

AC:

2769

AN:

1077310

Hom.:

134

Cov.:

AF XY:

0.00228

AC XY:

1162

AN XY:

509368

show subpopulations

African (AFR)

AF:

0.101

AC:

2279

AN:

22576

American (AMR)

AF:

0.00962

AC:

AN:

8112

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13982

East Asian (EAS)

AF:

0.00

AC:

AN:

25908

South Asian (SAS)

AF:

0.000100

AC:

AN:

19922

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21176

Middle Eastern (MID)

AF:

0.00444

AC:

AN:

2928

European-Non Finnish (NFE)

AF:

0.000121

AC:

111

AN:

919454

Other (OTH)

AF:

0.00661

AC:

286

AN:

43252

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

167

335

502

670

837

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

258

344

430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0270

AC:

4087

AN:

151126

Hom.:

187

Cov.:

AF XY:

0.0257

AC XY:

1900

AN XY:

73818

show subpopulations

African (AFR)

AF:

0.0931

AC:

3851

AN:

41368

American (AMR)

AF:

0.0111

AC:

169

AN:

15202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5076

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10294

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000355

AC:

AN:

67614

Other (OTH)

AF:

0.0186

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

190

380

571

761

951

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000867

Hom.:

Bravo

AF:

0.0302

ExAC

AF:

0.00112

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 13, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 18, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Jun 19, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GATA6 c.851C>G (p.Ala284Gly) results in a non-conservative amino acid change located in the GATA-type transcription activator, N-terminal domain (IPR008013) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0056 in 1228436 control chromosomes in the gnomAD database, including 321 homozygotes. The observed variant frequency is approximately 8929.73 fold of the estimated maximal expected allele frequency for a pathogenic variant in GATA6 causing Pancreatic Agenesis and Congenital Heart Defects phenotype (6.3e-07). To our knowledge, no occurrence of c.851C>G in individuals affected with Pancreatic Agenesis and Congenital Heart Defects and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 129135). Based on the evidence outlined above, the variant was classified as benign. -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Neonatal insulin-dependent diabetes mellitus

Benign:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

Potent mutations in GATA6 gene are associated with neonatal diabetes, decreased insulin production due to pancreatic aplasia or hypoplasia. Also associated with isolated cardiac abnormalities in children, like atrial septal defects.However no sufficient evidence is found to ascertain the role of this particular variant rs185325359 yet. -

Monogenic diabetes

Benign:1

Oct 27, 2015

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

ACMG Criteria: BS1, BP4 -

Atrioventricular septal defect 5

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Uncertain

0.67

D;D

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.43

.;T

MetaRNN

Benign

0.0035

T;T

MetaSVM

Benign

-0.44

MutationAssessor

Benign

0.40

N;N

PhyloP100

1.4

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.10

N;.

REVEL

Uncertain

0.31

Sift

Benign

0.44

T;.

Sift4G

Benign

0.37

T;T

Polyphen

0.73

P;P

Vest4

0.22

MVP

0.86

ClinPred

0.095

GERP RS

-0.31

Varity_R

0.034

gMVP

0.20

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over