17-68531661-T-G

Variant names:

• chr17-68531661-T-G
• rs8905
• NM_002734.5:c.*1212T>G

Variant summary

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

The NM_002734.5(PRKAR1A):​c.*1212T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 1,066,036 control chromosomes in the GnomAD database, including 8,001 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1271 hom., cov: 32)
  • Exomes 𝑓: 0.12 (6730 hom.)
• Consequence: PRKAR1A NM_002734.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.884
• Publications: 20 publications found

Genes affected

PRKAR1A (HGNC:9388): (protein kinase cAMP-dependent type I regulatory subunit alpha) cAMP is a signaling molecule important for a variety of cellular functions. cAMP exerts its effects by activating the cAMP-dependent protein kinase, which transduces the signal through phosphorylation of different target proteins. The inactive kinase holoenzyme is a tetramer composed of two regulatory and two catalytic subunits. cAMP causes the dissociation of the inactive holoenzyme into a dimer of regulatory subunits bound to four cAMP and two free monomeric catalytic subunits. Four different regulatory subunits and three catalytic subunits have been identified in humans. This gene encodes one of the regulatory subunits. This protein was found to be a tissue-specific extinguisher that down-regulates the expression of seven liver genes in hepatoma x fibroblast hybrids. Mutations in this gene cause Carney complex (CNC). This gene can fuse to the RET protooncogene by gene rearrangement and form the thyroid tumor-specific chimeric oncogene known as PTC2. A nonconventional nuclear localization sequence (NLS) has been found for this protein which suggests a role in DNA replication via the protein serving as a nuclear transport protein for the second subunit of the Replication Factor C (RFC40). Several alternatively spliced transcript variants encoding two different isoforms have been observed. [provided by RefSeq, Jan 2013]

PRKAR1A Gene-Disease associations (from GenCC):

• Acrodysostosis 1 with or without hormone resistance

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• acrodysostosis with multiple hormone resistance

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
• Carney complex, type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• pigmented nodular adrenocortical disease, primary, 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics
• acrodysostosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Carney complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial atrial myxoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• primary pigmented nodular adrenocortical disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 17-68531661-T-G is Benign according to our data. Variant chr17-68531661-T-G is described in ClinVar as Benign. ClinVar VariationId is 324806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAR1A	NM_002734.5	c.*1212T>G		3_prime_UTR_variant	Exon 11 of 11	ENST00000589228.6	NP_002725.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAR1A	ENST00000589228.6	c.*1212T>G		3_prime_UTR_variant	Exon 11 of 11	1	NM_002734.5	ENSP00000464977.2

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19410 AN: 152106 Hom.: 1269 Cov.: 32

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.104

Gnomad SAS AF: 0.0725

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.136

GnomAD4 exome AF: 0.121 AC: 110432 AN: 913812 Hom.: 6730 Cov.: 33 AF XY: 0.121 AC XY: 51079 AN XY: 421852

African (AFR) AF: 0.163 AC: 3200 AN: 19658

American (AMR) AF: 0.0809 AC: 281 AN: 3474

Ashkenazi Jewish (ASJ) AF: 0.0999 AC: 1023 AN: 10242

East Asian (EAS) AF: 0.119 AC: 1786 AN: 14982

South Asian (SAS) AF: 0.0826 AC: 1417 AN: 17146

European-Finnish (FIN) AF: 0.166 AC: 126 AN: 760

Middle Eastern (MID) AF: 0.130 AC: 274 AN: 2110

European-Non Finnish (NFE) AF: 0.121 AC: 98372 AN: 811402

Other (OTH) AF: 0.116 AC: 3953 AN: 34038

GnomAD4 genome AF: 0.128 AC: 19418 AN: 152224 Hom.: 1271 Cov.: 32 AF XY: 0.128 AC XY: 9527 AN XY: 74440

African (AFR) AF: 0.146 AC: 6082 AN: 41530

American (AMR) AF: 0.109 AC: 1661 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 352 AN: 3472

East Asian (EAS) AF: 0.104 AC: 538 AN: 5182

South Asian (SAS) AF: 0.0732 AC: 353 AN: 4822

European-Finnish (FIN) AF: 0.165 AC: 1745 AN: 10600

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.121 AC: 8221 AN: 68002

Other (OTH) AF: 0.135 AC: 284 AN: 2110

Alfa AF: 0.110 Hom.: 923

Bravo AF: 0.125

Asia WGS AF: 0.0730 AC: 255 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Acrodysostosis Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Carney complex Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	13
DANN	Benign	0.85
PhyloP100		0.88
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs8905; hg19: chr17-66527802;