18-20984360-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_005406.3(ROCK1):c.2480A>G(p.Gln827Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000943 in 1,601,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000095 ( 0 hom. )

Consequence

ROCK1
NM_005406.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.28

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 made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant where missense usually causes diseases, ROCK1

BP4

Computational evidence support a benign effect (MetaRNN=0.26345706).

BS2

High AC in GnomAd at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROCK1	NM_005406.3 linkuse as main transcript	c.2480A>G	p.Gln827Arg	missense_variant	20/33	ENST00000399799.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROCK1	ENST00000399799.3 linkuse as main transcript	c.2480A>G	p.Gln827Arg	missense_variant	20/33	1	NM_005406.3	P1
ROCK1	ENST00000635540.2 linkuse as main transcript	c.2480A>G	p.Gln827Arg	missense_variant, NMD_transcript_variant	20/34	5

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000127

AC:

AN:

244722

Hom.:

AF XY:

0.000121

AC XY:

AN XY:

132302

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000202

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000172

Gnomad FIN exome

AF:

0.0000948

Gnomad NFE exome

AF:

0.000188

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.0000952

AC:

138

AN:

1449138

Hom.:

Cov.:

AF XY:

0.0000984

AC XY:

AN XY:

721222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000578

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000710

Gnomad4 FIN exome

AF:

0.0000571

Gnomad4 NFE exome

AF:

0.0000903

Gnomad4 OTH exome

AF:

0.000217

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000246

Hom.:

Bravo

AF:

0.0000642

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000124

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2024

The c.2480A>G (p.Q827R) alteration is located in exon 20 (coding exon 20) of the ROCK1 gene. This alteration results from a A to G substitution at nucleotide position 2480, causing the glutamine (Q) at amino acid position 827 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.22

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Benign

0.13

Eigen

Benign

-0.013

Eigen_PC

Benign

0.17

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.0074

MetaRNN

Benign

0.26

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.91

REVEL

Benign

0.17

Sift

Benign

0.15

Sift4G

Benign

0.18

Polyphen

0.012

Vest4

0.56

MVP

0.79

MPC

0.65

ClinPred

0.11

GERP RS

4.9

Varity_R

0.27

gMVP

0.28

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over