4-81148883-C-T

Position:

• chr4-81148883-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_Moderate PM2 PP3_Strong PP5_Moderate

The NM_006259.3(PRKG2):​c.1154+1G>A variant causes a splice donor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKG2 NM_006259.3 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.14

Genes affected

PRKG2 (HGNC:9416): (protein kinase cGMP-dependent 2) This gene encodes a protein that belongs to the serine/threonine protein kinase family of proteins. The encoded protein binds to and inhibits the activation of several receptor tyrosine kinases. The membrane-bound protein is a regulator of intestinal secretion, bone growth and renin secretion. Alternate splicing results in multiple transcript variants encoding distinct isoforms whose regulatory N-termini differ in length but whose C-terminal catalytic domains are identical. [provided by RefSeq, May 2018]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.029707296 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 4-81148883-C-T is Pathogenic according to our data. Variant chr4-81148883-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2502276.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKG2	NM_006259.3	c.1154+1G>A		splice_donor_variant		ENST00000264399.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKG2	ENST00000264399.6	c.1154+1G>A		splice_donor_variant		5	NM_006259.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Acromesomelic dysplasia 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Endocrinology Unit / Unidade de Endocrinologia Genetica - LIM25, Universidade de Sao Paulo (USP)

May 11, 2023

The c.1154+1G>A variant occurs in a splice consensus site, predicted to alter splicing and result in a loss or disruption of normal protein function (PVS1). The variant is absent in most population databases (genomAD) and has a low frequency in the Brazilian population (MAF 0.000427, https://abraom.ib.usp.br/) (PM2). The patient's phenotype is compatible with the diagnosis of Acromesomelic dysplasia, without other genetic alterations that explain the phenotype (PP4). This variant was identified in homozygous in affected patient. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	1.0	D;D;D;D
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.35		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs995285513; hg19: chr4-82070037;