chr20-58843016-T-C

Variant names:

• chr20-58843016-T-C
• rs6123832
• NM_016592.5:c.*42+2130T>C

Variant summary

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

The NM_016592.5(GNAS):​c.*42+2130T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.584 in 152,078 control chromosomes in the GnomAD database, including 26,840 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 0.58 (26840 hom., cov: 32)
• Consequence: GNAS NM_016592.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.45
• Publications: 16 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-AS1 (HGNC:24872): (GNAS antisense RNA 1) This gene produces a paternally-imprinted antisense RNA transcript that helps regulate the GNAS complex locus, which encodes the alpha subunit of the stimulatory G protein. Defects in this gene are a cause of pseudohypoparathyroidism type Ib.[provided by RefSeq, Jun 2010]

GNAS-AS1 Gene-Disease associations (from GenCC):

• pseudohypoparathyroidism type 1B

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000293655 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.782 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016592.5. 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_016592.5	MANE Plus Clinical	c.*42+2130T>C		intron	N/A	NP_057676.1
	GNAS-AS1	NR_185847.1	MANE Select	n.280-471A>G		intron	N/A
	GNAS	NM_001410912.1		c.43+2130T>C		intron	N/A	NP_001397841.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	ENST00000371075.7	TSL:1 MANE Plus Clinical	c.*42+2130T>C		intron	N/A	ENSP00000360115.3
	GNAS-AS1	ENST00000718285.1	MANE Select	n.280-471A>G		intron	N/A
	GNAS	ENST00000663479.2		c.-39+1141T>C		intron	N/A	ENSP00000499353.2

Frequencies

GnomAD3 genomes AF: 0.583 AC: 88667 AN: 151960 Hom.: 26816 Cov.: 32

Gnomad AFR AF: 0.433

Gnomad AMI AF: 0.726

Gnomad AMR AF: 0.596

Gnomad ASJ AF: 0.512

Gnomad EAS AF: 0.803

Gnomad SAS AF: 0.681

Gnomad FIN AF: 0.692

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.635

Gnomad OTH AF: 0.558

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

GnomAD4 genome AF: 0.584 AC: 88743 AN: 152078 Hom.: 26840 Cov.: 32 AF XY: 0.589 AC XY: 43762 AN XY: 74338

African (AFR) AF: 0.433 AC: 17965 AN: 41478

American (AMR) AF: 0.596 AC: 9105 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.512 AC: 1772 AN: 3464

East Asian (EAS) AF: 0.803 AC: 4135 AN: 5152

South Asian (SAS) AF: 0.682 AC: 3285 AN: 4818

European-Finnish (FIN) AF: 0.692 AC: 7333 AN: 10594

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.635 AC: 43167 AN: 67978

Other (OTH) AF: 0.563 AC: 1187 AN: 2108

Alfa AF: 0.618 Hom.: 129487

Bravo AF: 0.571

Asia WGS AF: 0.709 AC: 2462 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.50
DANN	Benign	0.60
PhyloP100		-4.5
PromoterAI		-0.0013	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: rs6123832; hg19: chr20-57418071;