Genetic Variant NM_005406.3:c.2318C>G (chr18-20984522-G-C) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_005406.3(ROCK1):c.2318C>G(p.Thr773Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,608,498 control chromosomes in the GnomAD database, including 134 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0087 ( 11 hom., cov: 32)

Exomes 𝑓: 0.012 ( 123 hom. )

Consequence

ROCK1
NM_005406.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.46

Publications

9 publications found

Variant links:

Genes affected

ROCK1 (HGNC:10251): (Rho associated coiled-coil containing protein kinase 1) This gene encodes a protein serine/threonine kinase that is activated when bound to the GTP-bound form of Rho. The small GTPase Rho regulates formation of focal adhesions and stress fibers of fibroblasts, as well as adhesion and aggregation of platelets and lymphocytes by shuttling between the inactive GDP-bound form and the active GTP-bound form. Rho is also essential in cytokinesis and plays a role in transcriptional activation by serum response factor. This protein, a downstream effector of Rho, phosphorylates and activates LIM kinase, which in turn, phosphorylates cofilin, inhibiting its actin-depolymerizing activity. A pseudogene, related to this gene, is also located on chromosome 18. [provided by RefSeq, Aug 2015]

ROCK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0042348504).

BP6

Variant 18-20984522-G-C is Benign according to our data. Variant chr18-20984522-G-C is described in ClinVar as Benign. ClinVar VariationId is 777895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 1331 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005406.3. 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
	ROCK1	NM_005406.3	MANE Select	c.2318C>G	p.Thr773Ser	missense	Exon 20 of 33	NP_005397.1	Q13464

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROCK1	ENST00000399799.3	TSL:1 MANE Select	c.2318C>G	p.Thr773Ser	missense	Exon 20 of 33	ENSP00000382697.1	Q13464
	ROCK1	ENST00000635540.2	TSL:5	n.2318C>G		non_coding_transcript_exon	Exon 20 of 34	ENSP00000489185.1	A0A0U1RQV4

Frequencies

GnomAD3 genomes

AF:

0.00876

AC:

1332

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00266

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.00452

Gnomad ASJ

AF:

0.00722

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.0147

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0136

Gnomad OTH

AF:

0.00717

GnomAD2 exomes

AF:

0.00932

AC:

2297

AN:

246472

AF XY:

0.00904

show subpopulations

Gnomad AFR exome

AF:

0.00205

Gnomad AMR exome

AF:

0.00266

Gnomad ASJ exome

AF:

0.00740

Gnomad EAS exome

AF:

0.0000553

Gnomad FIN exome

AF:

0.0181

Gnomad NFE exome

AF:

0.0136

Gnomad OTH exome

AF:

0.0113

GnomAD4 exome

AF:

0.0122

AC:

17761

AN:

1456312

Hom.:

123

Cov.:

AF XY:

0.0120

AC XY:

8713

AN XY:

724564

show subpopulations

African (AFR)

AF:

0.00145

AC:

AN:

33002

American (AMR)

AF:

0.00277

AC:

120

AN:

43330

Ashkenazi Jewish (ASJ)

AF:

0.00636

AC:

165

AN:

25962

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39608

South Asian (SAS)

AF:

0.00414

AC:

353

AN:

85328

European-Finnish (FIN)

AF:

0.0172

AC:

908

AN:

52868

Middle Eastern (MID)

AF:

0.00387

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

0.0139

AC:

15488

AN:

1110374

Other (OTH)

AF:

0.0109

AC:

656

AN:

60156

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

757

1514

2272

3029

3786

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

568

1136

1704

2272

2840

<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:

0.00875

AC:

1331

AN:

152186

Hom.:

Cov.:

AF XY:

0.00829

AC XY:

617

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.00265

AC:

110

AN:

41520

American (AMR)

AF:

0.00451

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00722

AC:

AN:

3464

East Asian (EAS)

AF:

0.000580

AC:

AN:

5172

South Asian (SAS)

AF:

0.00435

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0147

AC:

155

AN:

10578

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0136

AC:

922

AN:

68012

Other (OTH)

AF:

0.00710

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

134

202

269

336

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00977

Hom.:

Bravo

AF:

0.00768

TwinsUK

AF:

0.0148

AC:

ALSPAC

AF:

0.0104

AC:

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.0130

AC:

112

ExAC

AF:

0.00942

AC:

1144

Asia WGS

AF:

0.00145

AC:

AN:

3470

EpiCase

AF:

0.0119

EpiControl

AF:

0.0117

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.74

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.077

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0042

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PhyloP100

2.5

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.53

REVEL

Benign

0.11

Sift

Benign

0.42

Sift4G

Benign

0.75

Polyphen

0.0010

Vest4

0.068

MutPred

0.095

Gain of phosphorylation at T773 (P = 0.0751)

MVP

0.31

MPC

0.41

ClinPred

0.0099

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.074

gMVP

0.046

Mutation Taster

=99/1

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over