20-58888417-C-G

Variant names:

• chr20-58888417-C-G
• rs6026578
• NM_080425.4:c.2069-7195C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_080425.4(GNAS):​c.2069-7195C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.606 in 152,136 control chromosomes in the GnomAD database, including 28,252 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.61 (28245 hom., cov: 32)
  • Exomes 𝑓: 0.59 (7 hom.)
• Consequence: GNAS NM_080425.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.43
• Publications: 22 publications found

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

ENSG00000225806 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.723 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080425.4. 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
	GNAS	NM_080425.4	MANE Plus Clinical	c.2069-7195C>G		intron	N/A	NP_536350.2
	GNAS	NM_016592.5	MANE Plus Clinical	c.*43-7195C>G		intron	N/A	NP_057676.1
	GNAS	NM_001410913.1		c.2069-7195C>G		intron	N/A	NP_001397842.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	ENST00000371100.9	TSL:5 MANE Plus Clinical	c.2069-7195C>G		intron	N/A	ENSP00000360141.3
	GNAS	ENST00000371075.7	TSL:1 MANE Plus Clinical	c.*43-7195C>G		intron	N/A	ENSP00000360115.3
	GNAS	ENST00000676826.2		c.2069-7195C>G		intron	N/A	ENSP00000504675.2

Frequencies

GnomAD3 genomes AF: 0.606 AC: 92070 AN: 151974 Hom.: 28224 Cov.: 32

Gnomad AFR AF: 0.513

Gnomad AMI AF: 0.658

Gnomad AMR AF: 0.641

Gnomad ASJ AF: 0.664

Gnomad EAS AF: 0.743

Gnomad SAS AF: 0.706

Gnomad FIN AF: 0.647

Gnomad MID AF: 0.617

Gnomad NFE AF: 0.626

Gnomad OTH AF: 0.624

GnomAD4 exome AF: 0.591 AC: 26 AN: 44 Hom.: 7 Cov.: 0 AF XY: 0.607 AC XY: 17 AN XY: 28

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.553 AC: 21 AN: 38

Other (OTH) AF: 1.00 AC: 4 AN: 4

GnomAD4 genome AF: 0.606 AC: 92132 AN: 152092 Hom.: 28245 Cov.: 32 AF XY: 0.609 AC XY: 45296 AN XY: 74332

African (AFR) AF: 0.513 AC: 21273 AN: 41470

American (AMR) AF: 0.641 AC: 9807 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.664 AC: 2303 AN: 3466

East Asian (EAS) AF: 0.743 AC: 3831 AN: 5156

South Asian (SAS) AF: 0.705 AC: 3396 AN: 4814

European-Finnish (FIN) AF: 0.647 AC: 6851 AN: 10582

Middle Eastern (MID) AF: 0.599 AC: 176 AN: 294

European-Non Finnish (NFE) AF: 0.626 AC: 42569 AN: 67990

Other (OTH) AF: 0.628 AC: 1326 AN: 2112

Alfa AF: 0.532 Hom.: 1670

Bravo AF: 0.605

Asia WGS AF: 0.745 AC: 2591 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.63
DANN	Benign	0.40
PhyloP100		-1.4
PromoterAI		-0.016	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6026578; hg19: chr20-57463472;