rs1483703733

Variant names:

Variant summary

Our verdict is The variant received -5 classification points (ACMG Germline Pathogenicity v2019). BS2BP4

The NM_004850.5(ROCK2):c.4130G>A (p.Arg1377Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000807 (AC=13) in the gnomAD database across 1,610,728 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000208. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

ROCK2
NM_004850.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.96

Publications

1 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: PanelApp Australia, ClinGen

ROCK2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_004850.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Supporting).

BS2

Pure AD gene with cumulative gnomAD AC ≥5 — observed in healthy adults (BS2); GnomAD homozygous count = 0.; Cumulative gnomAD AC = 13 (pure AD gene, not AR).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_004850.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROCK2	NM_004850.5	MANE Select	c.4130G>A	p.Arg1377Gln	missense	Exon 32 of 33	NP_004841.2
	ROCK2	NM_001321643.2		c.3872G>A	p.Arg1291Gln	missense	Exon 32 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.4130G>A	p.Arg1377Gln	missense	Exon 32 of 33	ENSP00000317985.6	O75116
ROCK2	ENST00000401753.5	TSL:1	c.3401G>A	p.Arg1134Gln	missense	Exon 28 of 29	ENSP00000385509.1	E9PF63
ROCK2	ENST00000944889.1		c.4307G>A	p.Arg1436Gln	missense	Exon 33 of 34	ENSP00000614948.1	A0ACI8UDE5

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151536

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000121

AC:

AN:

248086

AF XY:

0.00000743

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:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000754

AC:

AN:

1459192

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

725760

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33410

American (AMR)

AF:

0.0000225

AC:

AN:

44462

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26054

East Asian (EAS)

AF:

0.00

AC:

AN:

39626

South Asian (SAS)

AF:

0.00

AC:

AN:

85604

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00000900

AC:

AN:

1110684

Other (OTH)

AF:

0.00

AC:

AN:

60252

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151536

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

73956

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41242

American (AMR)

AF:

0.00

AC:

AN:

15218

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.000208

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67918

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

TOPMed (Bravo)

Data not reliable, filtered out with message: SVM

AF:

0.0000113

AC:

AN:

264690

Hom.:

ALFA (dbGaP/dbSNP Allele Frequency Aggregator)

AF:

0.0000636

AC:

AN:

47206

Hom.:

Case/control cohorts

Cohort

Cases

Controls

SCHEMA

(Schizophrenia)

0 / 102918AF: 0

3 / 183474AF: 0.0000163511

Allele count / allele number. AF is computed from the counts for ASC (not provided by the source).

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

Uncertain

0.52

BayesDel_addAF

Uncertain

0.046

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.067

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.013

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

PhyloP100

5.0

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.13

REVEL

Benign

0.27

Sift

Benign

0.34

Sift4G

Benign

0.58

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

popEVE

Benign

-3.4

(source)

VESM-3B

Benign

-5.7

(source)

FuncVEP CTI

Benign

0.040

(source)

AlphaGenome AVI

Pathogenic

(source)

GPN-Star LLR

-8.9

(source)

GPN-Star score

8.9

(source)

Mutation Taster

=71/29

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Pangolin (max)

Benign

0.020

(source)

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.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Case/control cohorts

ClinVar

Computational scores

Splicing

Publications

Other links and lift over