rs374626599

Variant names:

• chr7-550561-C-T
• rs374626599
• NM_001164760.2:c.1015G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-550561-C-T
• chr7-550561-C-G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001164760.2(PRKAR1B):​c.1015G>A​(p.Val339Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000438 in 1,599,762 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V339V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: PRKAR1B NM_001164760.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.33
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 5 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.1015G>A	p.Val339Ile	missense	Exon 11 of 11	NP_001158232.1	P31321
	PRKAR1B	NM_001164758.2		c.1015G>A	p.Val339Ile	missense	Exon 11 of 11	NP_001158230.1	P31321
	PRKAR1B	NM_001164759.1		c.1015G>A	p.Val339Ile	missense	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.1015G>A	p.Val339Ile	missense	Exon 11 of 11	ENSP00000440449.1	P31321
	PRKAR1B	ENST00000360274.8	TSL:1	c.1015G>A	p.Val339Ile	missense	Exon 11 of 11	ENSP00000353415.4	P31321
	PRKAR1B	ENST00000403562.5	TSL:1	c.1015G>A	p.Val339Ile	missense	Exon 11 of 11	ENSP00000385349.1	P31321

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000392 AC: 9 AN: 229746 AF XY: 0.0000318

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000577

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000774

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000449 AC: 65 AN: 1447614 Hom.: 0 Cov.: 31 AF XY: 0.0000514 AC XY: 37 AN XY: 719574

African (AFR) AF: 0.0000610 AC: 2 AN: 32810

American (AMR) AF: 0.00 AC: 0 AN: 42038

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25544

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39514

South Asian (SAS) AF: 0.00 AC: 0 AN: 84744

European-Finnish (FIN) AF: 0.0000195 AC: 1 AN: 51378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5496

European-Non Finnish (NFE) AF: 0.0000515 AC: 57 AN: 1106530

Other (OTH) AF: 0.0000672 AC: 4 AN: 59560

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152148 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74318

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68010

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.0000679 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.0000167 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Benign	1.2	L
PhyloP100		7.3
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.74	N
REVEL	Pathogenic	0.67
Sift	Benign	0.047	D
Sift4G	Benign	0.13	T
Polyphen		0.78	P
Vest4		0.61
MVP		0.93
MPC		1.1
ClinPred		0.30	T
GERP RS		4.7
Varity_R		0.24
gMVP		0.43
Mutation Taster		=49/51	disease causing

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: rs374626599; hg19: chr7-590198; COSMIC: COSV100816620;