18-22171206-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_005257.6(GATA6):c.62C>G(p.Ala21Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,599,824 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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. A21S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: GATA6 NM_005257.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.935

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06839186).
• BP6: Variant 18-22171206-C-G is Benign according to our data. Variant chr18-22171206-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 696465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 50 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA6	NM_005257.6	c.62C>G	p.Ala21Gly	missense_variant	2/7	ENST00000269216.10
GATA6	XM_047437483.1	c.62C>G	p.Ala21Gly	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA6	ENST00000269216.10	c.62C>G	p.Ala21Gly	missense_variant	2/7	1	NM_005257.6	P1
GATA6	ENST00000581694.1	c.62C>G	p.Ala21Gly	missense_variant	1/6	1		P1

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152038 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000204 AC: 47 AN: 230776 Hom.: 0 AF XY: 0.000117 AC XY: 15 AN XY: 127790

Gnomad AFR exome AF: 0.00124

Gnomad AMR exome AF: 0.000468

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000988

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000851

Gnomad OTH exome AF: 0.000171

GnomAD4 exome AF: 0.000104 AC: 150 AN: 1447670 Hom.: 1 Cov.: 31 AF XY: 0.0000902 AC XY: 65 AN XY: 720774

Gnomad4 AFR exome AF: 0.00170

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.000266

GnomAD4 genome AF: 0.000329 AC: 50 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74380

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.000567

ESP6500AA AF: 0.00117 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000225 AC: 27

EpiCase AF: 0.000109

EpiControl AF: 0.000297

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 10, 2020

- -

Atrioventricular septal defect 5 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.13
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.58	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Benign	0.068	T;T
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	0.81	L;L
MutationTaster	Benign	0.97	N;N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.4	N;.
REVEL	Uncertain	0.35
Sift	Uncertain	0.0040	D;.
Sift4G	Benign	0.082	T;T
Polyphen		0.93	P;P
Vest4		0.071
MVP		0.92
ClinPred		0.097	T
GERP RS		3.6
Varity_R		0.24
gMVP		0.18

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: rs139666654; hg19: chr18-19751167;