rs2295583

Variant names:

• chr20-58903393-A-T
• rs2295583
• NM_080425.4:c.2187-138A>T

Your query was ambiguous. Multiple possible variants found:

• chr20-58903393-A-T
• chr20-58903393-A-G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000516.7(GNAS):​c.258-138A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 791,184 control chromosomes in the GnomAD database, including 31,057 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7086 hom., cov: 31)
  • Exomes 𝑓: 0.26 (23971 hom.)
• Consequence: GNAS NM_000516.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.488
• Publications: 10 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P
• progressive osseous heteroplasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• pseudohypoparathyroidism type 1A

  Inheritance: AD, Mitochondrial Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• pseudohypoparathyroidism type 1B

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
• pseudohypoparathyroidism type 1C

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp
• pseudopseudohypoparathyroidism

  Inheritance: AD, Mitochondrial Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 20-58903393-A-T is Benign according to our data. Variant chr20-58903393-A-T is described in ClinVar as Benign. ClinVar VariationId is 1247589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000516.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	NM_080425.4	MANE Plus Clinical	c.2187-138A>T		intron	N/A	NP_536350.2	Q5JWF2-1
	GNAS	NM_000516.7	MANE Select	c.258-138A>T		intron	N/A	NP_000507.1	P63092-1
	GNAS	NM_016592.5	MANE Plus Clinical	c.*161-135A>T		intron	N/A	NP_057676.1	O95467-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	ENST00000371100.9	TSL:5 MANE Plus Clinical	c.2187-138A>T		intron	N/A	ENSP00000360141.3	Q5JWF2-1
	GNAS	ENST00000371085.8	TSL:1 MANE Select	c.258-138A>T		intron	N/A	ENSP00000360126.3	P63092-1
	GNAS	ENST00000371075.7	TSL:1 MANE Plus Clinical	c.*161-135A>T		intron	N/A	ENSP00000360115.3	O95467-1

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44781 AN: 152024 Hom.: 7078 Cov.: 31

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.161

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.0945

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.342

Gnomad MID AF: 0.279

Gnomad NFE AF: 0.289

Gnomad OTH AF: 0.280

GnomAD4 exome AF: 0.261 AC: 167072 AN: 639042 Hom.: 23971 Cov.: 8 AF XY: 0.256 AC XY: 87276 AN XY: 340836

African (AFR) AF: 0.370 AC: 6435 AN: 17388

American (AMR) AF: 0.151 AC: 5286 AN: 34934

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 6005 AN: 20552

East Asian (EAS) AF: 0.118 AC: 3836 AN: 32582

South Asian (SAS) AF: 0.132 AC: 8505 AN: 64532

European-Finnish (FIN) AF: 0.333 AC: 12100 AN: 36294

Middle Eastern (MID) AF: 0.264 AC: 883 AN: 3340

European-Non Finnish (NFE) AF: 0.291 AC: 115089 AN: 396096

Other (OTH) AF: 0.268 AC: 8933 AN: 33324

GnomAD4 genome AF: 0.295 AC: 44828 AN: 152142 Hom.: 7086 Cov.: 31 AF XY: 0.291 AC XY: 21668 AN XY: 74378

African (AFR) AF: 0.372 AC: 15417 AN: 41486

American (AMR) AF: 0.208 AC: 3183 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 1004 AN: 3472

East Asian (EAS) AF: 0.0940 AC: 487 AN: 5182

South Asian (SAS) AF: 0.134 AC: 649 AN: 4828

European-Finnish (FIN) AF: 0.342 AC: 3621 AN: 10578

Middle Eastern (MID) AF: 0.269 AC: 78 AN: 290

European-Non Finnish (NFE) AF: 0.289 AC: 19636 AN: 67990

Other (OTH) AF: 0.287 AC: 606 AN: 2112

Alfa AF: 0.201 Hom.: 504

Bravo AF: 0.289

Asia WGS AF: 0.182 AC: 633 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	10
DANN	Benign	0.90
PhyloP100		0.49
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2295583; hg19: chr20-57478448; COSMIC: COSV55681638; COSMIC: COSV55681638;