7-550562-A-G

Variant names:

• chr7-550562-A-G
• rs11545042
• NM_001164760.2:c.1014T>C

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.1014T>C​(p.Thr338Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 1,598,392 control chromosomes in the GnomAD database, including 14,221 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.15 (1813 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12408 hom.)
• Consequence: PRKAR1B NM_001164760.2 synonymous
• Clinical Significance: Benign no assertion criteria provided B:3
• Conservation: PhyloP100: -2.12
• Publications: 7 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=0.129).
• BP6: Variant 7-550562-A-G is Benign according to our data. Variant chr7-550562-A-G is described in ClinVar as [Benign]. Clinvar id is 1210100.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-2.12 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAR1B	NM_001164760.2	c.1014T>C	p.Thr338Thr	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.1014T>C	p.Thr338Thr	synonymous_variant	Exon 11 of 11	5	NM_001164760.2	ENSP00000440449.1

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22447 AN: 151996 Hom.: 1814 Cov.: 32

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.0945

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.0696

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.130

GnomAD2 exomes AF: 0.132 AC: 30002 AN: 228116 AF XY: 0.126

Gnomad AFR exome AF: 0.218

Gnomad AMR exome AF: 0.105

Gnomad ASJ exome AF: 0.0881

Gnomad EAS exome AF: 0.238

Gnomad FIN exome AF: 0.171

Gnomad NFE exome AF: 0.124

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.127 AC: 183052 AN: 1446278 Hom.: 12408 Cov.: 32 AF XY: 0.124 AC XY: 89057 AN XY: 718754

African (AFR) AF: 0.215 AC: 7044 AN: 32704

American (AMR) AF: 0.103 AC: 4295 AN: 41672

Ashkenazi Jewish (ASJ) AF: 0.0890 AC: 2270 AN: 25512

East Asian (EAS) AF: 0.253 AC: 9981 AN: 39416

South Asian (SAS) AF: 0.0663 AC: 5617 AN: 84704

European-Finnish (FIN) AF: 0.168 AC: 8615 AN: 51322

Middle Eastern (MID) AF: 0.0756 AC: 414 AN: 5478

European-Non Finnish (NFE) AF: 0.124 AC: 137474 AN: 1105966

Other (OTH) AF: 0.123 AC: 7342 AN: 59504

GnomAD4 genome AF: 0.148 AC: 22478 AN: 152114 Hom.: 1813 Cov.: 32 AF XY: 0.146 AC XY: 10889 AN XY: 74350

African (AFR) AF: 0.211 AC: 8756 AN: 41486

American (AMR) AF: 0.103 AC: 1580 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0945 AC: 328 AN: 3472

East Asian (EAS) AF: 0.230 AC: 1177 AN: 5124

South Asian (SAS) AF: 0.0689 AC: 332 AN: 4822

European-Finnish (FIN) AF: 0.157 AC: 1661 AN: 10610

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.121 AC: 8201 AN: 67978

Other (OTH) AF: 0.128 AC: 271 AN: 2116

Alfa AF: 0.125 Hom.: 408

Bravo AF: 0.148

Asia WGS AF: 0.144 AC: 501 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

Mar 05, 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	-0.84
CADD	Benign	0.021
DANN	Benign	0.46
PhyloP100		-2.1
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: rs11545042; hg19: chr7-590199; COSMIC: COSV64318316;