rs878884422

Variant names:

• chr17-68525810-A-G
• rs878884422
• NM_002734.5:c.606A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-68525810-A-G
• chr17-68525810-A-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2_Supporting

The NM_002734.5(PRKAR1A):​c.606A>G​(p.Glu202Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PRKAR1A NM_002734.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0850
• Publications: 0 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 17-68525810-A-G is Benign according to our data. Variant chr17-68525810-A-G is described in CliVar as Likely_benign. Clinvar id is 536904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-68525810-A-G is described in CliVar as Likely_benign. Clinvar id is 536904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-68525810-A-G is described in CliVar as Likely_benign. Clinvar id is 536904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-68525810-A-G is described in CliVar as Likely_benign. Clinvar id is 536904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-68525810-A-G is described in CliVar as Likely_benign. Clinvar id is 536904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-68525810-A-G is described in CliVar as Likely_benign. Clinvar id is 536904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-68525810-A-G is described in CliVar as Likely_benign. Clinvar id is 536904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-68525810-A-G is described in CliVar as Likely_benign. Clinvar id is 536904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-68525810-A-G is described in CliVar as Likely_benign. Clinvar id is 536904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-68525810-A-G is described in CliVar as Likely_benign. Clinvar id is 536904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-68525810-A-G is described in CliVar as Likely_benign. Clinvar id is 536904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-68525810-A-G is described in CliVar as Likely_benign. Clinvar id is 536904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-68525810-A-G is described in CliVar as Likely_benign. Clinvar id is 536904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-68525810-A-G is described in CliVar as Likely_benign. Clinvar id is 536904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-68525810-A-G is described in CliVar as Likely_benign. Clinvar id is 536904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-68525810-A-G is described in CliVar as Likely_benign. Clinvar id is 536904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-68525810-A-G is described in CliVar as Likely_benign. Clinvar id is 536904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-68525810-A-G is described in CliVar as Likely_benign. Clinvar id is 536904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-68525810-A-G is described in CliVar as Likely_benign. Clinvar id is 536904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-68525810-A-G is described in CliVar as Likely_benign. Clinvar id is 536904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-68525810-A-G is described in CliVar as Likely_benign. Clinvar id is 536904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.085 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000329 (5/152030) while in subpopulation AMR AF = 0.000197 (3/15256). AF 95% confidence interval is 0.0000529. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAR1A	NM_002734.5	c.606A>G	p.Glu202Glu	synonymous_variant	Exon 7 of 11	ENST00000589228.6	NP_002725.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAR1A	ENST00000589228.6	c.606A>G	p.Glu202Glu	synonymous_variant	Exon 7 of 11	1	NM_002734.5	ENSP00000464977.2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152030 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461776 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727194

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111944

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152030 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74290

African (AFR) AF: 0.0000483 AC: 2 AN: 41366

American (AMR) AF: 0.000197 AC: 3 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Carney complex, type 1 Benign:1

Jun 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Jun 11, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	7.2
DANN	Benign	0.50
PhyloP100		-0.085
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs878884422; hg19: chr17-66521951;