chr7-550610-T-G

Variant names:

• chr7-550610-T-G
• rs28585978
• NM_001164760.2:c.974-8A>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001164760.2(PRKAR1B):​c.974-8A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,548,320 control chromosomes in the GnomAD database, including 870 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.022 (121 hom., cov: 32)
  • Exomes 𝑓: 0.010 (749 hom.)
• Consequence: PRKAR1B NM_001164760.2 splice_region, intron
• Scores: Splicing: ADA: 0.00001114
• Clinical Significance: Benign no assertion criteria provided B:3
• Conservation: PhyloP100: 0.532

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]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 7-550610-T-G is Benign according to our data. Variant chr7-550610-T-G is described in ClinVar as [Benign]. Clinvar id is 1209930.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-550610-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAR1B	NM_001164760.2	c.974-8A>C		splice_region_variant, intron_variant	Intron 10 of 10	ENST00000537384.6	NP_001158232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAR1B	ENST00000537384.6	c.974-8A>C		splice_region_variant, intron_variant	Intron 10 of 10	5	NM_001164760.2	ENSP00000440449.1

Frequencies

GnomAD3 genomes AF: 0.0219 AC: 3323 AN: 151396 Hom.: 122 Cov.: 32

Gnomad AFR AF: 0.0477

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00755

Gnomad ASJ AF: 0.00664

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.0176

Gnomad FIN AF: 0.00124

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.00425

Gnomad OTH AF: 0.0207

GnomAD2 exomes AF: 0.0220 AC: 4008 AN: 182266 AF XY: 0.0206

Gnomad AFR exome AF: 0.0454

Gnomad AMR exome AF: 0.00445

Gnomad ASJ exome AF: 0.00376

Gnomad EAS exome AF: 0.166

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.00396

Gnomad OTH exome AF: 0.0152

GnomAD4 exome AF: 0.0100 AC: 14005 AN: 1396804 Hom.: 749 Cov.: 32 AF XY: 0.0101 AC XY: 6972 AN XY: 689328

Gnomad4 AFR exome AF: 0.0499 AC: 1556 AN: 31164

Gnomad4 AMR exome AF: 0.00472 AC: 162 AN: 34300

Gnomad4 ASJ exome AF: 0.00393 AC: 88 AN: 22384

Gnomad4 EAS exome AF: 0.179 AC: 6964 AN: 38888

Gnomad4 SAS exome AF: 0.0141 AC: 1067 AN: 75908

Gnomad4 FIN exome AF: 0.00150 AC: 72 AN: 47972

Gnomad4 NFE exome AF: 0.00285 AC: 3093 AN: 1084198

Gnomad4 Remaining exome AF: 0.0159 AC: 911 AN: 57396

GnomAD4 genome AF: 0.0220 AC: 3330 AN: 151516 Hom.: 121 Cov.: 32 AF XY: 0.0229 AC XY: 1692 AN XY: 74004

Gnomad4 AFR AF: 0.0479 AC: 0.0479213 AN: 0.0479213

Gnomad4 AMR AF: 0.00748 AC: 0.00747541 AN: 0.00747541

Gnomad4 ASJ AF: 0.00664 AC: 0.00663589 AN: 0.00663589

Gnomad4 EAS AF: 0.152 AC: 0.152217 AN: 0.152217

Gnomad4 SAS AF: 0.0169 AC: 0.0169456 AN: 0.0169456

Gnomad4 FIN AF: 0.00124 AC: 0.00123527 AN: 0.00123527

Gnomad4 NFE AF: 0.00425 AC: 0.00424653 AN: 0.00424653

Gnomad4 OTH AF: 0.0200 AC: 0.02 AN: 0.02

Alfa AF: 0.0131 Hom.: 7

Bravo AF: 0.0240

Asia WGS AF: 0.0750 AC: 263 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: no assertion criteria provided

Submissions by phenotype

not specified Benign:2

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University 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	-0.91
CADD	Benign	3.5
DANN	Benign	0.49
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000011
dbscSNV1_RF	Benign	0.0040
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

Publications

LitVar

Other links and lift over

dbSNP: rs28585978; hg19: chr7-590247; COSMIC: COSV64319195;