7-550592-T-C

Variant names:

• chr7-550592-T-C
• rs28626752
• NM_001164760.2:c.984A>G

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.984A>G​(p.Ala328Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,579,800 control chromosomes in the GnomAD database, including 885 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.022 (124 hom., cov: 32)
  • Exomes 𝑓: 0.010 (761 hom.)
• Consequence: PRKAR1B NM_001164760.2 synonymous
• Clinical Significance: Benign no assertion criteria provided B:3
• Conservation: PhyloP100: -3.64
• Publications: 4 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=0.033).
• BP6: Variant 7-550592-T-C is Benign according to our data. Variant chr7-550592-T-C is described in ClinVar as Benign. ClinVar VariationId is 1210095.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-3.64 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164760.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAR1B	NM_001164760.2	MANE Select	c.984A>G	p.Ala328Ala	synonymous	Exon 11 of 11	NP_001158232.1	P31321
	PRKAR1B	NM_001164758.2		c.984A>G	p.Ala328Ala	synonymous	Exon 11 of 11	NP_001158230.1	P31321
	PRKAR1B	NM_001164759.1		c.984A>G	p.Ala328Ala	synonymous	Exon 11 of 11	NP_001158231.1	P31321

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAR1B	ENST00000537384.6	TSL:5 MANE Select	c.984A>G	p.Ala328Ala	synonymous	Exon 11 of 11	ENSP00000440449.1	P31321
	PRKAR1B	ENST00000360274.8	TSL:1	c.984A>G	p.Ala328Ala	synonymous	Exon 11 of 11	ENSP00000353415.4	P31321
	PRKAR1B	ENST00000403562.5	TSL:1	c.984A>G	p.Ala328Ala	synonymous	Exon 11 of 11	ENSP00000385349.1	P31321

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3358 AN: 151804 Hom.: 125 Cov.: 32

Gnomad AFR AF: 0.0483

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00767

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00424

Gnomad OTH AF: 0.0215

GnomAD2 exomes AF: 0.0214 AC: 4460 AN: 208320 AF XY: 0.0201

Gnomad AFR exome AF: 0.0481

Gnomad AMR exome AF: 0.00426

Gnomad ASJ exome AF: 0.00342

Gnomad EAS exome AF: 0.169

Gnomad FIN exome AF: 0.00138

Gnomad NFE exome AF: 0.00399

Gnomad OTH exome AF: 0.0150

GnomAD4 exome AF: 0.0101 AC: 14436 AN: 1427878 Hom.: 761 Cov.: 32 AF XY: 0.0102 AC XY: 7258 AN XY: 708444

African (AFR) AF: 0.0510 AC: 1632 AN: 32010

American (AMR) AF: 0.00454 AC: 176 AN: 38790

Ashkenazi Jewish (ASJ) AF: 0.00372 AC: 90 AN: 24162

East Asian (EAS) AF: 0.179 AC: 7043 AN: 39238

South Asian (SAS) AF: 0.0144 AC: 1174 AN: 81510

European-Finnish (FIN) AF: 0.00154 AC: 77 AN: 50116

Middle Eastern (MID) AF: 0.0209 AC: 105 AN: 5026

European-Non Finnish (NFE) AF: 0.00290 AC: 3190 AN: 1098310

Other (OTH) AF: 0.0162 AC: 949 AN: 58716

GnomAD4 genome AF: 0.0222 AC: 3368 AN: 151922 Hom.: 124 Cov.: 32 AF XY: 0.0230 AC XY: 1712 AN XY: 74280

African (AFR) AF: 0.0486 AC: 2012 AN: 41428

American (AMR) AF: 0.00759 AC: 116 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3470

East Asian (EAS) AF: 0.152 AC: 776 AN: 5098

South Asian (SAS) AF: 0.0168 AC: 81 AN: 4814

European-Finnish (FIN) AF: 0.00123 AC: 13 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00424 AC: 288 AN: 67904

Other (OTH) AF: 0.0208 AC: 44 AN: 2112

Alfa AF: 0.00638 Hom.: 3

Bravo AF: 0.0241

Asia WGS AF: 0.0760 AC: 264 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	PRKAR1B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.086
DANN	Benign	0.45
PhyloP100		-3.6
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: rs28626752; hg19: chr7-590229; COSMIC: COSV64319192;