7-550564-T-A

Variant names:

• chr7-550564-T-A
• NM_001164760.2:c.1012A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001164760.2(PRKAR1B):​c.1012A>T​(p.Thr338Ser) 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 (★). Synonymous variant affecting the same amino acid position (i.e. T338T) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKAR1B NM_001164760.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.43
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAR1B	NM_001164760.2	c.1012A>T	p.Thr338Ser	missense_variant	Exon 11 of 11	ENST00000537384.6	NP_001158232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAR1B	ENST00000537384.6	c.1012A>T	p.Thr338Ser	missense_variant	Exon 11 of 11	5	NM_001164760.2	ENSP00000440449.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 04, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;D;D;D;D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;.;.;.;.
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	1.1	L;L;L;L;L
PhyloP100		7.4
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.7	D;D;D;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.023	D;D;D;D;D
Sift4G	Benign	0.61	T;T;T;T;T
Polyphen		0.95	P;P;P;P;P
Vest4		0.84
MutPred		0.67		Loss of glycosylation at T338 (P = 0.0565);Loss of glycosylation at T338 (P = 0.0565);Loss of glycosylation at T338 (P = 0.0565);Loss of glycosylation at T338 (P = 0.0565);Loss of glycosylation at T338 (P = 0.0565);
MVP		0.99
MPC		1.1
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.62
gMVP		0.57
Mutation Taster		=23/77	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: chr7-590201;