Genetic Variant ROCK2:p.Thr431Ile (chr2-11218994-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004850.5(ROCK2):c.1292C>T(p.Thr431Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000309 in 1,295,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T431S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000031 ( 0 hom. )

Consequence

ROCK2
NM_004850.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.02

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07319173).

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.1292C>T	p.Thr431Ile	missense	Exon 10 of 33	NP_004841.2
	ROCK2	NM_001321643.2		c.1034C>T	p.Thr345Ile	missense	Exon 10 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.1292C>T	p.Thr431Ile	missense	Exon 10 of 33	ENSP00000317985.6	O75116
ROCK2	ENST00000401753.5	TSL:1	c.563C>T	p.Thr188Ile	missense	Exon 6 of 29	ENSP00000385509.1	E9PF63
ROCK2	ENST00000944889.1		c.1292C>T	p.Thr431Ile	missense	Exon 10 of 34	ENSP00000614948.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000309

AC:

AN:

1295448

Hom.:

Cov.:

AF XY:

0.00000309

AC XY:

AN XY:

647938

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30332

American (AMR)

AF:

0.00

AC:

AN:

33832

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23084

East Asian (EAS)

AF:

0.00

AC:

AN:

37596

South Asian (SAS)

AF:

0.00

AC:

AN:

72164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5090

European-Non Finnish (NFE)

AF:

0.00000404

AC:

AN:

988902

Other (OTH)

AF:

0.00

AC:

AN:

54028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.52

M_CAP

Benign

0.029

MetaRNN

Benign

0.073

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

PhyloP100

1.0

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.7

REVEL

Benign

0.057

Sift

Benign

0.14

Sift4G

Benign

0.18

Polyphen

0.0

Vest4

0.096

MutPred

0.22

Loss of phosphorylation at T431 (P = 0.0247)

MVP

0.20

MPC

0.85

ClinPred

0.30

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.049

gMVP

0.14

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over