7-550568-C-T

Variant names:

• chr7-550568-C-T
• rs370829885
• NM_001164760.2:c.1008G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001164760.2(PRKAR1B):​c.1008G>A​(p.Ala336Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,593,558 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (4 hom.)
• Consequence: PRKAR1B NM_001164760.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -4.08
• Publications: 2 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.013).
• BP6: Variant 7-550568-C-T is Benign according to our data. Variant chr7-550568-C-T is described in ClinVar as Benign. ClinVar VariationId is 786768.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-4.08 with no splicing effect.
• BS2: High AC in GnomAd4 at 216 AD gene.

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.1008G>A	p.Ala336Ala	synonymous	Exon 11 of 11	NP_001158232.1	P31321
	PRKAR1B	NM_001164758.2		c.1008G>A	p.Ala336Ala	synonymous	Exon 11 of 11	NP_001158230.1	P31321
	PRKAR1B	NM_001164759.1		c.1008G>A	p.Ala336Ala	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.1008G>A	p.Ala336Ala	synonymous	Exon 11 of 11	ENSP00000440449.1	P31321
	PRKAR1B	ENST00000360274.8	TSL:1	c.1008G>A	p.Ala336Ala	synonymous	Exon 11 of 11	ENSP00000353415.4	P31321
	PRKAR1B	ENST00000403562.5	TSL:1	c.1008G>A	p.Ala336Ala	synonymous	Exon 11 of 11	ENSP00000385349.1	P31321

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 216 AN: 152050 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00119

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00158 AC: 353 AN: 223822 AF XY: 0.00152

Gnomad AFR exome AF: 0.000434

Gnomad AMR exome AF: 0.000756

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000176

Gnomad FIN exome AF: 0.00804

Gnomad NFE exome AF: 0.00157

Gnomad OTH exome AF: 0.000942

GnomAD4 exome AF: 0.00141 AC: 2039 AN: 1441390 Hom.: 4 Cov.: 32 AF XY: 0.00136 AC XY: 975 AN XY: 716018

African (AFR) AF: 0.000523 AC: 17 AN: 32510

American (AMR) AF: 0.000661 AC: 27 AN: 40856

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25202

East Asian (EAS) AF: 0.000228 AC: 9 AN: 39406

South Asian (SAS) AF: 0.0000595 AC: 5 AN: 84048

European-Finnish (FIN) AF: 0.00880 AC: 450 AN: 51112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5330

European-Non Finnish (NFE) AF: 0.00133 AC: 1465 AN: 1103700

Other (OTH) AF: 0.00111 AC: 66 AN: 59226

GnomAD4 genome AF: 0.00142 AC: 216 AN: 152168 Hom.: 2 Cov.: 32 AF XY: 0.00184 AC XY: 137 AN XY: 74398

African (AFR) AF: 0.000193 AC: 8 AN: 41536

American (AMR) AF: 0.000588 AC: 9 AN: 15298

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

East Asian (EAS) AF: 0.000389 AC: 2 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.0106 AC: 113 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00119 AC: 81 AN: 67968

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000697 Hom.: 1

Bravo AF: 0.000684

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	4.4
DANN	Benign	0.79
PhyloP100		-4.1
Mutation Taster		=97/3	polymorphism

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: rs370829885; hg19: chr7-590205; COSMIC: COSV64319199;