20-58909186-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_080425.4(GNAS):c.2484C>T(p.Ile828Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0241 in 1,613,874 control chromosomes in the GnomAD database, including 2,621 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.078 ( 1313 hom., cov: 32)

Exomes 𝑓: 0.018 ( 1308 hom. )

Consequence

GNAS
NM_080425.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.27

Publications

19 publications found

Variant links:

COSMIC-nc: COSV99671336

Genes affected

GNAS (HGNC:4392): (GNAS complex locus) This locus has a highly complex imprinted expression pattern. It gives rise to maternally, paternally, and biallelically expressed transcripts that are derived from four alternative promoters and 5' exons. Some transcripts contain a differentially methylated region (DMR) at their 5' exons, and this DMR is commonly found in imprinted genes and correlates with transcript expression. An antisense transcript is produced from an overlapping locus on the opposite strand. One of the transcripts produced from this locus, and the antisense transcript, are paternally expressed noncoding RNAs, and may regulate imprinting in this region. In addition, one of the transcripts contains a second overlapping ORF, which encodes a structurally unrelated protein - Alex. Alternative splicing of downstream exons is also observed, which results in different forms of the stimulatory G-protein alpha subunit, a key element of the classical signal transduction pathway linking receptor-ligand interactions with the activation of adenylyl cyclase and a variety of cellular reponses. Multiple transcript variants encoding different isoforms have been found for this gene. Mutations in this gene result in pseudohypoparathyroidism type 1a, pseudohypoparathyroidism type 1b, Albright hereditary osteodystrophy, pseudopseudohypoparathyroidism, McCune-Albright syndrome, progressive osseus heteroplasia, polyostotic fibrous dysplasia of bone, and some pituitary tumors. [provided by RefSeq, Aug 2012]

GNAS Gene-Disease associations (from GenCC):

McCune-Albright syndrome
Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
progressive osseous heteroplasia
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, NO_KNOWN Submitted by: G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
pseudohypoparathyroidism type 1B
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
pseudohypoparathyroidism type 1C
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
pseudopseudohypoparathyroidism
Inheritance: AD, Mitochondrial Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
pseudohypoparathyroidism type 1A
Inheritance: Mitochondrial, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

GNAS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.3).

BP6

Variant 20-58909186-C-T is Benign according to our data. Variant chr20-58909186-C-T is described in ClinVar as Benign. ClinVar VariationId is 1166173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.27 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
GNAS	NM_080425.4 link	c.2484C>T	p.Ile828Ile	synonymous_variant	Exon 7 of 13	ENST00000371100.9	NP_536350.2
GNAS	NM_000516.7 link	c.555C>T	p.Ile185Ile	synonymous_variant	Exon 7 of 13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5 link	c.*461C>T		3_prime_UTR_variant	Exon 7 of 13	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GNAS	ENST00000371100.9 link	c.2484C>T	p.Ile828Ile	synonymous_variant	Exon 7 of 13	5	NM_080425.4	ENSP00000360141.3
GNAS	ENST00000371085.8 link	c.555C>T	p.Ile185Ile	synonymous_variant	Exon 7 of 13	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000676826.2 link	c.2487C>T	p.Ile829Ile	synonymous_variant	Exon 7 of 13			ENSP00000504675.2
GNAS	ENST00000371102.8 link	c.2442C>T	p.Ile814Ile	synonymous_variant	Exon 6 of 12	5		ENSP00000360143.4
GNAS	ENST00000354359.12 link	c.558C>T	p.Ile186Ile	synonymous_variant	Exon 7 of 13	1		ENSP00000346328.7
GNAS	ENST00000371095.7 link	c.513C>T	p.Ile171Ile	synonymous_variant	Exon 6 of 12	1		ENSP00000360136.3
GNAS	ENST00000470512.6 link	c.381C>T	p.Ile127Ile	synonymous_variant	Exon 7 of 13	5		ENSP00000499552.2
GNAS	ENST00000480232.6 link	c.381C>T	p.Ile127Ile	synonymous_variant	Exon 8 of 14	5		ENSP00000499545.2
GNAS	ENST00000663479.2 link	c.381C>T	p.Ile127Ile	synonymous_variant	Exon 7 of 13			ENSP00000499353.2
GNAS	ENST00000462499.6 link	c.336C>T	p.Ile112Ile	synonymous_variant	Exon 6 of 12	2		ENSP00000499758.2
GNAS	ENST00000467227.6 link	c.336C>T	p.Ile112Ile	synonymous_variant	Exon 7 of 13	3		ENSP00000499681.2
GNAS	ENST00000478585.6 link	c.336C>T	p.Ile112Ile	synonymous_variant	Exon 6 of 12	2		ENSP00000499762.2
GNAS	ENST00000481039.6 link	c.336C>T	p.Ile112Ile	synonymous_variant	Exon 6 of 12	5		ENSP00000499767.2
GNAS	ENST00000485673.6 link	c.336C>T	p.Ile112Ile	synonymous_variant	Exon 6 of 12	5		ENSP00000499334.2
GNAS	ENST00000488546.6 link	c.336C>T	p.Ile112Ile	synonymous_variant	Exon 6 of 12	5		ENSP00000499332.2
GNAS	ENST00000492907.6 link	c.336C>T	p.Ile112Ile	synonymous_variant	Exon 6 of 12	3		ENSP00000499443.2
GNAS	ENST00000371075.7 link	c.*461C>T		3_prime_UTR_variant	Exon 7 of 13	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000453292.7 link	c.*416C>T		3_prime_UTR_variant	Exon 6 of 12	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes

AF:

0.0782

AC:

11885

AN:

152072

Hom.:

1310

Cov.:

show subpopulations

Gnomad AFR

AF:

0.246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0325

Gnomad ASJ

AF:

0.0228

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0114

Gnomad FIN

AF:

0.00386

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0134

Gnomad OTH

AF:

0.0569

GnomAD2 exomes

AF:

0.0277

AC:

6968

AN:

251482

AF XY:

0.0232

show subpopulations

Gnomad AFR exome

AF:

0.252

Gnomad AMR exome

AF:

0.0182

Gnomad ASJ exome

AF:

0.0199

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00323

Gnomad NFE exome

AF:

0.0131

Gnomad OTH exome

AF:

0.0241

GnomAD4 exome

AF:

0.0185

AC:

26974

AN:

1461684

Hom.:

1308

Cov.:

AF XY:

0.0176

AC XY:

12792

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.260

AC:

8700

AN:

33456

American (AMR)

AF:

0.0198

AC:

885

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0212

AC:

555

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.0110

AC:

946

AN:

86246

European-Finnish (FIN)

AF:

0.00300

AC:

160

AN:

53420

Middle Eastern (MID)

AF:

0.0395

AC:

228

AN:

5766

European-Non Finnish (NFE)

AF:

0.0125

AC:

13891

AN:

1111854

Other (OTH)

AF:

0.0266

AC:

1605

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

1450

2899

4349

5798

7248

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

650

1300

1950

2600

3250

<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:

0.0783

AC:

11909

AN:

152190

Hom.:

1313

Cov.:

AF XY:

0.0755

AC XY:

5623

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.246

AC:

10195

AN:

41456

American (AMR)

AF:

0.0324

AC:

496

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0228

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.0116

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00386

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0134

AC:

909

AN:

68014

Other (OTH)

AF:

0.0563

AC:

119

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

481

963

1444

1926

2407

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

232

348

464

580

<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:

0.0312

Hom.:

868

Bravo

AF:

0.0875

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.0166

EpiControl

AF:

0.0160

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 26, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.85

PhyloP100

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

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