7-550473-C-T

Variant names:

• chr7-550473-C-T
• NM_001164760.2:c.1103G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001164760.2(PRKAR1B):​c.1103G>A​(p.Arg368Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PRKAR1B NM_001164760.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.35
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.771

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.1103G>A	p.Arg368Lys	missense	Exon 11 of 11	NP_001158232.1	P31321
	PRKAR1B	NM_001164758.2		c.1103G>A	p.Arg368Lys	missense	Exon 11 of 11	NP_001158230.1	P31321
	PRKAR1B	NM_001164759.1		c.1103G>A	p.Arg368Lys	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.1103G>A	p.Arg368Lys	missense	Exon 11 of 11	ENSP00000440449.1	P31321
	PRKAR1B	ENST00000360274.8	TSL:1	c.1103G>A	p.Arg368Lys	missense	Exon 11 of 11	ENSP00000353415.4	P31321
	PRKAR1B	ENST00000403562.5	TSL:1	c.1103G>A	p.Arg368Lys	missense	Exon 11 of 11	ENSP00000385349.1	P31321

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.4
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.58	P
Vest4		0.72
MutPred		0.54		Gain of methylation at R368 (P = 0.0163)
MVP		0.95
MPC		1.1
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.89
gMVP		0.70
Mutation Taster		=25/75	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

hg19: chr7-590110;