7-551488-C-G

Variant names:

• chr7-551488-C-G
• rs71518309
• NM_001164760.2:c.892-18G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001164760.2(PRKAR1B):​c.892-18G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.513 in 1,548,482 control chromosomes in the GnomAD database, including 208,000 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.58 (25999 hom., cov: 33)
  • Exomes 𝑓: 0.51 (182001 hom.)
• Consequence: PRKAR1B NM_001164760.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -0.208
• Publications: 6 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 7-551488-C-G is Benign according to our data. Variant chr7-551488-C-G is described in ClinVar as [Benign]. Clinvar id is 1210049.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAR1B	NM_001164760.2	c.892-18G>C		intron_variant	Intron 9 of 10	ENST00000537384.6	NP_001158232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAR1B	ENST00000537384.6	c.892-18G>C		intron_variant	Intron 9 of 10	5	NM_001164760.2	ENSP00000440449.1

Frequencies

GnomAD3 genomes AF: 0.577 AC: 87462 AN: 151620 Hom.: 25964 Cov.: 33

Gnomad AFR AF: 0.722

Gnomad AMI AF: 0.482

Gnomad AMR AF: 0.644

Gnomad ASJ AF: 0.506

Gnomad EAS AF: 0.578

Gnomad SAS AF: 0.366

Gnomad FIN AF: 0.548

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.498

Gnomad OTH AF: 0.574

GnomAD2 exomes AF: 0.538 AC: 81516 AN: 151622 AF XY: 0.518

Gnomad AFR exome AF: 0.725

Gnomad AMR exome AF: 0.714

Gnomad ASJ exome AF: 0.493

Gnomad EAS exome AF: 0.575

Gnomad FIN exome AF: 0.555

Gnomad NFE exome AF: 0.500

Gnomad OTH exome AF: 0.531

GnomAD4 exome AF: 0.506 AC: 707029 AN: 1396744 Hom.: 182001 Cov.: 42 AF XY: 0.500 AC XY: 344815 AN XY: 689052

African (AFR) AF: 0.718 AC: 22939 AN: 31932

American (AMR) AF: 0.702 AC: 25050 AN: 35692

Ashkenazi Jewish (ASJ) AF: 0.499 AC: 12527 AN: 25122

East Asian (EAS) AF: 0.615 AC: 22137 AN: 36020

South Asian (SAS) AF: 0.363 AC: 28778 AN: 79346

European-Finnish (FIN) AF: 0.545 AC: 26069 AN: 47828

Middle Eastern (MID) AF: 0.504 AC: 2483 AN: 4922

European-Non Finnish (NFE) AF: 0.498 AC: 537239 AN: 1078018

Other (OTH) AF: 0.515 AC: 29807 AN: 57864

GnomAD4 genome AF: 0.577 AC: 87542 AN: 151738 Hom.: 25999 Cov.: 33 AF XY: 0.577 AC XY: 42769 AN XY: 74162

African (AFR) AF: 0.722 AC: 29784 AN: 41242

American (AMR) AF: 0.644 AC: 9842 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.506 AC: 1754 AN: 3464

East Asian (EAS) AF: 0.578 AC: 2974 AN: 5148

South Asian (SAS) AF: 0.366 AC: 1764 AN: 4824

European-Finnish (FIN) AF: 0.548 AC: 5803 AN: 10592

Middle Eastern (MID) AF: 0.507 AC: 149 AN: 294

European-Non Finnish (NFE) AF: 0.498 AC: 33832 AN: 67878

Other (OTH) AF: 0.569 AC: 1201 AN: 2112

Alfa AF: 0.446 Hom.: 2110

Bravo AF: 0.593

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

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

- -

not provided Benign:1

Mar 11, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.0
DANN	Benign	0.29
PhyloP100		-0.21
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs71518309; hg19: chr7-591125; COSMIC: COSV64318354;