Genetic Variant NM_004850.5:c.1682A>G (chr2-11215328-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004850.5(ROCK2):c.1682A>G(p.Gln561Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,442,376 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ROCK2
NM_004850.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.20

Publications

0 publications found

Variant links:

Genes affected

ROCK2 (HGNC:10252): (Rho associated coiled-coil containing protein kinase 2) The protein encoded by this gene is a serine/threonine kinase that regulates cytokinesis, smooth muscle contraction, the formation of actin stress fibers and focal adhesions, and the activation of the c-fos serum response element. This protein, which is an isozyme of ROCK1 is a target for the small GTPase Rho. [provided by RefSeq, Jul 2008]

ROCK2 Gene-Disease associations (from GenCC):

congenital heart disease
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, PanelApp Australia

ROCK2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004850.5. 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
	ROCK2	NM_004850.5	MANE Select	c.1682A>G	p.Gln561Arg	missense	Exon 15 of 33	NP_004841.2
	ROCK2	NM_001321643.2		c.1424A>G	p.Gln475Arg	missense	Exon 15 of 33	NP_001308572.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ROCK2	ENST00000315872.11	TSL:1 MANE Select	c.1682A>G	p.Gln561Arg	missense	Exon 15 of 33	ENSP00000317985.6	O75116
ROCK2	ENST00000401753.5	TSL:1	c.953A>G	p.Gln318Arg	missense	Exon 11 of 29	ENSP00000385509.1	E9PF63
ROCK2	ENST00000944889.1		c.1682A>G	p.Gln561Arg	missense	Exon 15 of 34	ENSP00000614948.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000424

AC:

AN:

235972

AF XY:

0.00000782

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000916

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1442376

Hom.:

Cov.:

AF XY:

0.00000279

AC XY:

AN XY:

717536

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32470

American (AMR)

AF:

0.00

AC:

AN:

41308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25596

East Asian (EAS)

AF:

0.00

AC:

AN:

39558

South Asian (SAS)

AF:

0.00

AC:

AN:

82948

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52470

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5586

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1102804

Other (OTH)

AF:

0.00

AC:

AN:

59636

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Uncertain

0.027

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.019

MetaRNN

Uncertain

0.57

MetaSVM

Benign

-0.78

MutationAssessor

Benign

1.6

PhyloP100

6.2

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.17

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.0040

Polyphen

0.90

Vest4

0.74

MutPred

0.12

Gain of MoRF binding (P = 0.0199)

MVP

0.61

MPC

0.81

ClinPred

0.91

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.40

gMVP

0.43

Mutation Taster

=37/63

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over