7-550511-G-A

Variant names:

• chr7-550511-G-A
• rs28488947
• NM_001164760.2:c.1065C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BA1

The NM_001164760.2(PRKAR1B):​c.1065C>T​(p.Phe355Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,603,114 control chromosomes in the GnomAD database, including 827 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.017 (92 hom., cov: 33)
  • Exomes 𝑓: 0.0096 (735 hom.)
• Consequence: PRKAR1B NM_001164760.2 synonymous
• Clinical Significance: Benign no assertion criteria provided B:3
• Conservation: PhyloP100: -0.440
• Publications: 5 publications found

Genes affected

PRKAR1B (HGNC:9390): (protein kinase cAMP-dependent type I regulatory subunit beta) The protein encoded by this gene is a regulatory subunit of cyclic AMP-dependent protein kinase A (PKA), which is involved in the signaling pathway of the second messenger cAMP. Two regulatory and two catalytic subunits form the PKA holoenzyme, disbands after cAMP binding. The holoenzyme is involved in many cellular events, including ion transport, metabolism, and transcription. Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Aug 2015]

PRKAR1B Gene-Disease associations (from GenCC):

• Marbach-Schaaf neurodevelopmental syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• PRKAR1B-related neurodegenerative dementia with intermediate filaments

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (REVEL=0.089).
• BP6: Variant 7-550511-G-A is Benign according to our data. Variant chr7-550511-G-A is described in ClinVar as [Benign]. Clinvar id is 1210096.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.44 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAR1B	NM_001164760.2	c.1065C>T	p.Phe355Phe	synonymous_variant	Exon 11 of 11	ENST00000537384.6	NP_001158232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAR1B	ENST00000537384.6	c.1065C>T	p.Phe355Phe	synonymous_variant	Exon 11 of 11	5	NM_001164760.2	ENSP00000440449.1

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 2530 AN: 152118 Hom.: 93 Cov.: 33

Gnomad AFR AF: 0.0293

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00421

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.0194 AC: 4412 AN: 227768 AF XY: 0.0186

Gnomad AFR exome AF: 0.0302

Gnomad AMR exome AF: 0.00349

Gnomad ASJ exome AF: 0.00306

Gnomad EAS exome AF: 0.168

Gnomad FIN exome AF: 0.00151

Gnomad NFE exome AF: 0.00398

Gnomad OTH exome AF: 0.0150

GnomAD4 exome AF: 0.00958 AC: 13898 AN: 1450876 Hom.: 735 Cov.: 31 AF XY: 0.00982 AC XY: 7079 AN XY: 720660

African (AFR) AF: 0.0301 AC: 1002 AN: 33304

American (AMR) AF: 0.00378 AC: 164 AN: 43414

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 97 AN: 25868

East Asian (EAS) AF: 0.179 AC: 7047 AN: 39280

South Asian (SAS) AF: 0.0145 AC: 1222 AN: 84426

European-Finnish (FIN) AF: 0.00158 AC: 81 AN: 51408

Middle Eastern (MID) AF: 0.0198 AC: 114 AN: 5758

European-Non Finnish (NFE) AF: 0.00294 AC: 3252 AN: 1107532

Other (OTH) AF: 0.0153 AC: 919 AN: 59886

GnomAD4 genome AF: 0.0167 AC: 2535 AN: 152238 Hom.: 92 Cov.: 33 AF XY: 0.0176 AC XY: 1307 AN XY: 74438

African (AFR) AF: 0.0295 AC: 1224 AN: 41548

American (AMR) AF: 0.00529 AC: 81 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 23 AN: 3472

East Asian (EAS) AF: 0.151 AC: 776 AN: 5136

South Asian (SAS) AF: 0.0166 AC: 80 AN: 4826

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10628

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00421 AC: 286 AN: 68004

Other (OTH) AF: 0.0175 AC: 37 AN: 2114

Alfa AF: 0.00932 Hom.: 10

Bravo AF: 0.0180

Asia WGS AF: 0.0740 AC: 258 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: no assertion criteria provided

Submissions by phenotype

not specified Benign:2

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PRKAR1B-related disorder Benign:1

Aug 02, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	1.7
DANN	Benign	0.87
PhyloP100		-0.44
Mutation Taster		=96/4	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: rs28488947; hg19: chr7-590148;