20-22582036-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_021784.5(FOXA2):c.1206A>G(p.Gln402=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.877 in 1,613,626 control chromosomes in the GnomAD database, including 621,472 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.91 (62772 hom., cov: 32)
  • Exomes 𝑓: 0.87 (558700 hom.)
• Consequence: FOXA2 NM_021784.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0760

Genes affected

FOXA2 (HGNC:5022): (forkhead box A2) This gene encodes a member of the forkhead class of DNA-binding proteins. These hepatocyte nuclear factors are transcriptional activators for liver-specific genes such as albumin and transthyretin, and they also interact with chromatin. Similar family members in mice have roles in the regulation of metabolism and in the differentiation of the pancreas and liver. This gene has been linked to sporadic cases of maturity-onset diabetes of the young. Transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 20-22582036-T-C is Benign according to our data. Variant chr20-22582036-T-C is described in ClinVar as [Benign]. Clinvar id is 1300560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.076 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXA2	NM_021784.5	c.1206A>G	p.Gln402=	synonymous_variant	2/2	ENST00000419308.7
FOXA2	NM_153675.3	c.1188A>G	p.Gln396=	synonymous_variant	3/3
FOXA2	XM_047440133.1	c.1188A>G	p.Gln396=	synonymous_variant	3/3
FOXA2	XM_047440134.1	c.1098A>G	p.Gln366=	synonymous_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXA2	ENST00000419308.7	c.1206A>G	p.Gln402=	synonymous_variant	2/2	1	NM_021784.5	P4
FOXA2	ENST00000377115.4	c.1188A>G	p.Gln396=	synonymous_variant	3/3	1		A1

Frequencies

GnomAD3 genomes AF: 0.907 AC: 137923 AN: 152074 Hom.: 62712 Cov.: 32

Gnomad AFR AF: 0.975

Gnomad AMI AF: 0.905

Gnomad AMR AF: 0.908

Gnomad ASJ AF: 0.887

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.967

Gnomad FIN AF: 0.879

Gnomad MID AF: 0.848

Gnomad NFE AF: 0.860

Gnomad OTH AF: 0.894

GnomAD3 exomes AF: 0.901 AC: 225247 AN: 249896 Hom.: 101863 AF XY: 0.900 AC XY: 121607 AN XY: 135094

Gnomad AFR exome AF: 0.976

Gnomad AMR exome AF: 0.937

Gnomad ASJ exome AF: 0.887

Gnomad EAS exome AF: 0.999

Gnomad SAS exome AF: 0.956

Gnomad FIN exome AF: 0.872

Gnomad NFE exome AF: 0.857

Gnomad OTH exome AF: 0.878

GnomAD4 exome AF: 0.873 AC: 1276442 AN: 1461434 Hom.: 558700 Cov.: 91 AF XY: 0.876 AC XY: 636719 AN XY: 727024

Gnomad4 AFR exome AF: 0.977

Gnomad4 AMR exome AF: 0.936

Gnomad4 ASJ exome AF: 0.888

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.957

Gnomad4 FIN exome AF: 0.872

Gnomad4 NFE exome AF: 0.856

Gnomad4 OTH exome AF: 0.884

GnomAD4 genome AF: 0.907 AC: 138042 AN: 152192 Hom.: 62772 Cov.: 32 AF XY: 0.910 AC XY: 67654 AN XY: 74384

Gnomad4 AFR AF: 0.975

Gnomad4 AMR AF: 0.909

Gnomad4 ASJ AF: 0.887

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.966

Gnomad4 FIN AF: 0.879

Gnomad4 NFE AF: 0.860

Gnomad4 OTH AF: 0.895

Alfa AF: 0.874 Hom.: 81838

Bravo AF: 0.912

Asia WGS AF: 0.980 AC: 3408 AN: 3478

EpiCase AF: 0.859

EpiControl AF: 0.858

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	6.5
Dann	Benign	0.47

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: rs1212275; hg19: chr20-22562674;