chr7-551429-C-T

Variant names:

• chr7-551429-C-T
• rs147220037
• NM_001164760.2:c.933G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001164760.2(PRKAR1B):​c.933G>A​(p.Glu311Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00207 in 1,560,526 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (10 hom.)
• Consequence: PRKAR1B NM_001164760.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.989
• 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.074).
• BP6: Variant 7-551429-C-T is Benign according to our data. Variant chr7-551429-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 791569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.989 with no splicing effect.
• BS2: High AC in GnomAd4 at 337 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.933G>A	p.Glu311Glu	synonymous	Exon 10 of 11	NP_001158232.1	P31321
	PRKAR1B	NM_001164758.2		c.933G>A	p.Glu311Glu	synonymous	Exon 10 of 11	NP_001158230.1	P31321
	PRKAR1B	NM_001164759.1		c.933G>A	p.Glu311Glu	synonymous	Exon 10 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.933G>A	p.Glu311Glu	synonymous	Exon 10 of 11	ENSP00000440449.1	P31321
	PRKAR1B	ENST00000360274.8	TSL:1	c.933G>A	p.Glu311Glu	synonymous	Exon 10 of 11	ENSP00000353415.4	P31321
	PRKAR1B	ENST00000403562.5	TSL:1	c.933G>A	p.Glu311Glu	synonymous	Exon 10 of 11	ENSP00000385349.1	P31321

Frequencies

GnomAD3 genomes AF: 0.00222 AC: 337 AN: 152136 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00225

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00267 AC: 448 AN: 167896 AF XY: 0.00252

Gnomad AFR exome AF: 0.000289

Gnomad AMR exome AF: 0.000790

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0102

Gnomad NFE exome AF: 0.00224

Gnomad OTH exome AF: 0.00219

GnomAD4 exome AF: 0.00205 AC: 2888 AN: 1408272 Hom.: 10 Cov.: 31 AF XY: 0.00211 AC XY: 1466 AN XY: 695428

African (AFR) AF: 0.000244 AC: 8 AN: 32758

American (AMR) AF: 0.000688 AC: 25 AN: 36346

Ashkenazi Jewish (ASJ) AF: 0.0106 AC: 266 AN: 25168

East Asian (EAS) AF: 0.00 AC: 0 AN: 37578

South Asian (SAS) AF: 0.000337 AC: 27 AN: 80038

European-Finnish (FIN) AF: 0.0105 AC: 510 AN: 48424

Middle Eastern (MID) AF: 0.00163 AC: 9 AN: 5532

European-Non Finnish (NFE) AF: 0.00176 AC: 1913 AN: 1084058

Other (OTH) AF: 0.00223 AC: 130 AN: 58370

GnomAD4 genome AF: 0.00221 AC: 337 AN: 152254 Hom.: 1 Cov.: 33 AF XY: 0.00255 AC XY: 190 AN XY: 74444

African (AFR) AF: 0.0000963 AC: 4 AN: 41528

American (AMR) AF: 0.000719 AC: 11 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 51 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.0106 AC: 113 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00225 AC: 153 AN: 68004

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00303 Hom.: 0

Bravo AF: 0.00144

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	5.5
DANN	Benign	0.87
PhyloP100		0.99
Mutation Taster		=100/0	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: rs147220037; hg19: chr7-591066;