rs2145288

Variant names:

• chr20-58869154-C-A
• rs2145288
• NM_016592.5:c.*43-26458C>A

Your query was ambiguous. Multiple possible variants found:

• chr20-58869154-C-A
• chr20-58869154-C-G
• chr20-58869154-C-T

Variant summary

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

The NM_016592.5(GNAS):​c.*43-26458C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.733 in 152,202 control chromosomes in the GnomAD database, including 40,988 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 0.73 (40988 hom., cov: 34)
• Consequence: GNAS NM_016592.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.236
• Publications: 11 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.797 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_016592.5	c.*43-26458C>A		intron_variant	Intron 1 of 12	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371075.7	c.*43-26458C>A		intron_variant	Intron 1 of 12	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000676826.2	c.2068+13821C>A		intron_variant	Intron 1 of 12			ENSP00000504675.2
GNAS	ENST00000371102.8	c.2068+13821C>A		intron_variant	Intron 1 of 11	5		ENSP00000360143.4
GNAS	ENST00000663479.2	c.-38-26458C>A		intron_variant	Intron 1 of 12			ENSP00000499353.2
GNAS	ENST00000462499.6	c.-38-26458C>A		intron_variant	Intron 1 of 11	2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.-39+25080C>A		intron_variant	Intron 2 of 12	3		ENSP00000499681.2
GNAS	ENST00000453292.7	c.*43-26458C>A		intron_variant	Intron 1 of 11	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes AF: 0.733 AC: 111452 AN: 152084 Hom.: 40947 Cov.: 34

Gnomad AFR AF: 0.713

Gnomad AMI AF: 0.819

Gnomad AMR AF: 0.696

Gnomad ASJ AF: 0.633

Gnomad EAS AF: 0.818

Gnomad SAS AF: 0.779

Gnomad FIN AF: 0.762

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.744

Gnomad OTH AF: 0.708

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.733 AC: 111546 AN: 152202 Hom.: 40988 Cov.: 34 AF XY: 0.733 AC XY: 54511 AN XY: 74414

African (AFR) AF: 0.714 AC: 29628 AN: 41520

American (AMR) AF: 0.697 AC: 10650 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.633 AC: 2194 AN: 3468

East Asian (EAS) AF: 0.818 AC: 4242 AN: 5188

South Asian (SAS) AF: 0.779 AC: 3757 AN: 4824

European-Finnish (FIN) AF: 0.762 AC: 8066 AN: 10590

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.744 AC: 50574 AN: 68004

Other (OTH) AF: 0.711 AC: 1502 AN: 2114

Alfa AF: 0.735 Hom.: 22809

Bravo AF: 0.726

Asia WGS AF: 0.780 AC: 2715 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.1
DANN	Benign	0.54
PhyloP100		0.24
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: rs2145288; hg19: chr20-57444209;