chr7-727208-ACCTGGACGAC-A

Variant names:

• chr7-727208-ACCTGGACGAC-A
• rs1554248887
• NM_017802.4:c.489_498delCCTGGACGAC

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001164760.2(PRKAR1B):​c.-31_-23+1delGTCGTCCAGG variant causes a splice donor, 5 prime UTR, intron change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKAR1B NM_001164760.2 splice_donor, 5_prime_UTR, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.58
• Publications: 0 publications found

Genes affected

DNAAF5 (HGNC:26013): (dynein axonemal assembly factor 5) The protein encoded by this gene is essential for the preassembly or stability of axonemal dynein arms, and is found only in organisms with motile cilia and flagella. Mutations in this gene are associated with primary ciliary dyskinesia-18, a disorder characterized by abnormalities of motile cilia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2013]

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_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06282722 fraction of the gene.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-727208-ACCTGGACGAC-A is Pathogenic according to our data. Variant chr7-727208-ACCTGGACGAC-A is described in ClinVar as Pathogenic. ClinVar VariationId is 454865.Status of the report is criteria_provided_single_submitter, 1 stars.

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
	DNAAF5	NM_017802.4	MANE Select	c.489_498delCCTGGACGAC	p.His163GlnfsTer43	frameshift	Exon 1 of 13	NP_060272.3
	PRKAR1B	NM_001164760.2	MANE Select	c.-31_-23+1delGTCGTCCAGG		splice_region	Exon 1 of 11	NP_001158232.1	P31321
	PRKAR1B	NM_001164760.2	MANE Select	c.-31_-23+1delGTCGTCCAGG		splice_donor 5_prime_UTR intron	Exon 1 of 11	NP_001158232.1	P31321

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF5	ENST00000297440.11	TSL:1 MANE Select	c.489_498delCCTGGACGAC	p.His163GlnfsTer43	frameshift	Exon 1 of 13	ENSP00000297440.6	Q86Y56-1
	PRKAR1B	ENST00000537384.6	TSL:5 MANE Select	c.-31_-23+1delGTCGTCCAGG		splice_region	Exon 1 of 11	ENSP00000440449.1	P31321
	PRKAR1B	ENST00000537384.6	TSL:5 MANE Select	c.-31_-23+1delGTCGTCCAGG		splice_donor 5_prime_UTR intron	Exon 1 of 11	ENSP00000440449.1	P31321

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.6
Mutation Taster		=16/184	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1554248887;

hg19: chr7-766845;