7-550610-T-G

Variant names:

• chr7-550610-T-G
• rs28585978
• NM_001164760.2:c.974-8A>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001164760.2(PRKAR1B):​c.974-8A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,548,320 control chromosomes in the GnomAD database, including 870 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.022 (121 hom., cov: 32)
  • Exomes 𝑓: 0.010 (749 hom.)
• Consequence: PRKAR1B NM_001164760.2 splice_region, intron
• Scores: Splicing: ADA: 0.00001114
• Clinical Significance: Benign no assertion criteria provided B:3
• Conservation: PhyloP100: 0.532
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 7-550610-T-G is Benign according to our data. Variant chr7-550610-T-G is described in ClinVar as Benign. ClinVar VariationId is 1209930.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

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.974-8A>C		splice_region intron	N/A	NP_001158232.1	P31321
	PRKAR1B	NM_001164758.2		c.974-8A>C		splice_region intron	N/A	NP_001158230.1	P31321
	PRKAR1B	NM_001164759.1		c.974-8A>C		splice_region intron	N/A	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.974-8A>C		splice_region intron	N/A	ENSP00000440449.1	P31321
	PRKAR1B	ENST00000360274.8	TSL:1	c.974-8A>C		splice_region intron	N/A	ENSP00000353415.4	P31321
	PRKAR1B	ENST00000403562.5	TSL:1	c.974-8A>C		splice_region intron	N/A	ENSP00000385349.1	P31321

Frequencies

GnomAD3 genomes AF: 0.0219 AC: 3323 AN: 151396 Hom.: 122 Cov.: 32

Gnomad AFR AF: 0.0477

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00755

Gnomad ASJ AF: 0.00664

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.0176

Gnomad FIN AF: 0.00124

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.00425

Gnomad OTH AF: 0.0207

GnomAD2 exomes AF: 0.0220 AC: 4008 AN: 182266 AF XY: 0.0206

Gnomad AFR exome AF: 0.0454

Gnomad AMR exome AF: 0.00445

Gnomad ASJ exome AF: 0.00376

Gnomad EAS exome AF: 0.166

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.00396

Gnomad OTH exome AF: 0.0152

GnomAD4 exome AF: 0.0100 AC: 14005 AN: 1396804 Hom.: 749 Cov.: 32 AF XY: 0.0101 AC XY: 6972 AN XY: 689328

African (AFR) AF: 0.0499 AC: 1556 AN: 31164

American (AMR) AF: 0.00472 AC: 162 AN: 34300

Ashkenazi Jewish (ASJ) AF: 0.00393 AC: 88 AN: 22384

East Asian (EAS) AF: 0.179 AC: 6964 AN: 38888

South Asian (SAS) AF: 0.0141 AC: 1067 AN: 75908

European-Finnish (FIN) AF: 0.00150 AC: 72 AN: 47972

Middle Eastern (MID) AF: 0.0200 AC: 92 AN: 4594

European-Non Finnish (NFE) AF: 0.00285 AC: 3093 AN: 1084198

Other (OTH) AF: 0.0159 AC: 911 AN: 57396

GnomAD4 genome AF: 0.0220 AC: 3330 AN: 151516 Hom.: 121 Cov.: 32 AF XY: 0.0229 AC XY: 1692 AN XY: 74004

African (AFR) AF: 0.0479 AC: 1978 AN: 41276

American (AMR) AF: 0.00748 AC: 114 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00664 AC: 23 AN: 3466

East Asian (EAS) AF: 0.152 AC: 776 AN: 5098

South Asian (SAS) AF: 0.0169 AC: 81 AN: 4780

European-Finnish (FIN) AF: 0.00124 AC: 13 AN: 10524

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.00425 AC: 288 AN: 67820

Other (OTH) AF: 0.0200 AC: 42 AN: 2100

Alfa AF: 0.0131 Hom.: 7

Bravo AF: 0.0240

Asia WGS AF: 0.0750 AC: 263 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	PRKAR1B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.5
DANN	Benign	0.49
PhyloP100		0.53
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000011
dbscSNV1_RF	Benign	0.0040
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: rs28585978; hg19: chr7-590247; COSMIC: COSV64319195;