4-81140668-A-C

Position:

• chr4-81140668-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3 PP5_Moderate

The NM_006259.3(PRKG2):​c.1409T>G​(p.Val470Gly) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKG2 NM_006259.3 missense, splice_region
• Scores: Splicing: ADA: 0.4410
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.19

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PRKG2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.748
• PP5: Variant 4-81140668-A-C is Pathogenic according to our data. Variant chr4-81140668-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2501812.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.1409T>G	p.Val470Gly	missense_variant, splice_region_variant	12/19	ENST00000264399.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKG2	ENST00000264399.6	c.1409T>G	p.Val470Gly	missense_variant, splice_region_variant	12/19	5	NM_006259.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Acromesomelic dysplasia 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Acualanaylab, Acibadem University

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.060	T;T;T;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D;.;T
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.72	D;D;D;D
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.2	D;D;D;.
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.65
MutPred		0.61		.;Loss of stability (P = 0.002);Loss of stability (P = 0.002);.;
MVP		0.75
MPC		1.6
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.91
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.44
dbscSNV1_RF	Benign	0.56
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-82061822;