ENST00000676826.2:c.1376C>G

Variant names:

• chr20-58854641-C-G
• rs148033592
• NM_080425.4:c.1376C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000676826.2(GNAS):​c.1376C>G​(p.Pro459Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,505,282 control chromosomes in the GnomAD database, including 10 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (4 hom., cov: 33)
  • Exomes 𝑓: 0.015 (6 hom.)
• Consequence: GNAS ENST00000676826.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 0.480
• Publications: 20 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024326742).
• BP6: Variant 20-58854641-C-G is Benign according to our data. Variant chr20-58854641-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 134480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0856 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000676826.2. 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.1376C>G	p.Pro459Arg	missense	Exon 1 of 13	NP_536350.2	Q5JWF2-1
	GNAS	NM_016592.5	MANE Plus Clinical	c.*42+13755C>G		intron	N/A	NP_057676.1	O95467-1
	GNAS	NM_001410913.1		c.1376C>G	p.Pro459Arg	missense	Exon 1 of 12	NP_001397842.1	Q5JWE9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	ENST00000371100.9	TSL:5 MANE Plus Clinical	c.1376C>G	p.Pro459Arg	missense	Exon 1 of 13	ENSP00000360141.3	Q5JWF2-1
	GNAS	ENST00000676826.2		c.1376C>G	p.Pro459Arg	missense	Exon 1 of 13	ENSP00000504675.2	A0A7I2V5R6
	GNAS	ENST00000371102.8	TSL:5	c.1376C>G	p.Pro459Arg	missense	Exon 1 of 12	ENSP00000360143.4	Q5JWF2-2

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1577 AN: 149672 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0285

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00641

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00409

Gnomad SAS AF: 0.00795

Gnomad FIN AF: 0.000755

Gnomad MID AF: 0.00980

Gnomad NFE AF: 0.00383

Gnomad OTH AF: 0.00920

GnomAD2 exomes AF: 0.00947 AC: 1187 AN: 125312 AF XY: 0.00972

Gnomad AFR exome AF: 0.0336

Gnomad AMR exome AF: 0.0135

Gnomad ASJ exome AF: 0.00230

Gnomad EAS exome AF: 0.00303

Gnomad FIN exome AF: 0.00351

Gnomad NFE exome AF: 0.00662

Gnomad OTH exome AF: 0.00889

GnomAD4 exome AF: 0.0148 AC: 20063 AN: 1355510 Hom.: 6 Cov.: 34 AF XY: 0.0143 AC XY: 9580 AN XY: 669260

African (AFR) AF: 0.0885 AC: 2446 AN: 27632

American (AMR) AF: 0.0124 AC: 429 AN: 34640

Ashkenazi Jewish (ASJ) AF: 0.00161 AC: 40 AN: 24876

East Asian (EAS) AF: 0.00175 AC: 62 AN: 35442

South Asian (SAS) AF: 0.0111 AC: 865 AN: 78084

European-Finnish (FIN) AF: 0.000650 AC: 22 AN: 33836

Middle Eastern (MID) AF: 0.00778 AC: 39 AN: 5014

European-Non Finnish (NFE) AF: 0.0145 AC: 15314 AN: 1059326

Other (OTH) AF: 0.0149 AC: 846 AN: 56660

GnomAD4 genome AF: 0.0106 AC: 1586 AN: 149772 Hom.: 4 Cov.: 33 AF XY: 0.0104 AC XY: 759 AN XY: 73294

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0286 AC: 1138 AN: 39798

American (AMR) AF: 0.00647 AC: 98 AN: 15156

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00410 AC: 21 AN: 5118

South Asian (SAS) AF: 0.00796 AC: 38 AN: 4774

European-Finnish (FIN) AF: 0.000755 AC: 8 AN: 10596

Middle Eastern (MID) AF: 0.0106 AC: 3 AN: 284

European-Non Finnish (NFE) AF: 0.00383 AC: 259 AN: 67582

Other (OTH) AF: 0.00960 AC: 20 AN: 2084

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0356 Hom.: 1

ExAC AF: 0.00410 AC: 325

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	GNAS-related disorder (1)
-	-	1	not specified (2)
-	-	1	Pseudopseudohypoparathyroidism;C0242292:McCune-Albright syndrome;C0334041:Progressive osseous heteroplasia;C1857451:ACTH-independent macronodular adrenal hyperplasia 1;C1864100:Pseudohypoparathyroidism type 1B;C2932716:Pseudohypoparathyroidism type 1C;C3494506:Pseudohypoparathyroidism type I A;C4540135:Pituitary adenoma 3, multiple types (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	8.4
DANN	Benign	0.97
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.085	N
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.91	T
PhyloP100		0.48
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.024
Sift	Benign	0.10	T
Sift4G	Benign	0.50	T
Vest4		0.097
MVP		0.21
ClinPred		0.0055	T
GERP RS		0.082
Varity_R		0.15
Mutation Taster		=96/4	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs148033592; hg19: chr20-57429696; COSMIC: COSV58326923; COSMIC: COSV58326923;