7-551390-G-A

Variant names:

• chr7-551390-G-A
• rs144566354
• NM_001164760.2:c.972C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP6_Moderate BP7 BS2

The NM_001164760.2(PRKAR1B):​c.972C>T​(p.Phe324Phe) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000358 in 1,556,964 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: PRKAR1B NM_001164760.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.0001591
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.458
• Publications: 1 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 -7 ACMG points.

• BP6: Variant 7-551390-G-A is Benign according to our data. Variant chr7-551390-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 787312.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.458 with no splicing effect.
• BS2: High AC in GnomAd4 at 280 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAR1B	NM_001164760.2	c.972C>T	p.Phe324Phe	splice_region_variant, synonymous_variant	Exon 10 of 11	ENST00000537384.6	NP_001158232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAR1B	ENST00000537384.6	c.972C>T	p.Phe324Phe	splice_region_variant, synonymous_variant	Exon 10 of 11	5	NM_001164760.2	ENSP00000440449.1

Frequencies

GnomAD3 genomes AF: 0.00184 AC: 280 AN: 152108 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00633

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

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: 0.0000294

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000439 AC: 72 AN: 164108 AF XY: 0.000298

Gnomad AFR exome AF: 0.00555

Gnomad AMR exome AF: 0.000279

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000235

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000467

Gnomad OTH exome AF: 0.000444

GnomAD4 exome AF: 0.000197 AC: 277 AN: 1404738 Hom.: 0 Cov.: 31 AF XY: 0.000164 AC XY: 114 AN XY: 693364

African (AFR) AF: 0.00625 AC: 203 AN: 32476

American (AMR) AF: 0.000305 AC: 11 AN: 36046

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25156

East Asian (EAS) AF: 0.0000539 AC: 2 AN: 37130

South Asian (SAS) AF: 0.0000752 AC: 6 AN: 79760

European-Finnish (FIN) AF: 0.0000207 AC: 1 AN: 48254

Middle Eastern (MID) AF: 0.000365 AC: 2 AN: 5472

European-Non Finnish (NFE) AF: 0.0000176 AC: 19 AN: 1082206

Other (OTH) AF: 0.000567 AC: 33 AN: 58238

GnomAD4 genome AF: 0.00184 AC: 280 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.00165 AC XY: 123 AN XY: 74422

African (AFR) AF: 0.00631 AC: 262 AN: 41518

American (AMR) AF: 0.000850 AC: 13 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67990

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000574 Hom.: 0

Bravo AF: 0.00206

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PRKAR1B-related disorder Benign:1

Mar 12, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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	-0.59
CADD	Benign	0.064
DANN	Benign	0.84
PhyloP100		-0.46
Mutation Taster		=65/35	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.35
SpliceAI score (max)		0.010		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: rs144566354; hg19: chr7-591027;