18-20984522-G-C

Position:

• chr18-20984522-G-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0087 (11 hom., cov: 32)
  • Exomes 𝑓: 0.012 (123 hom.)
• Consequence: ROCK1 NM_005406.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.46

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ROCK1
• 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 id is 777895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1331 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROCK1	NM_005406.3	c.2318C>G	p.Thr773Ser	missense_variant	20/33	ENST00000399799.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROCK1	ENST00000399799.3	c.2318C>G	p.Thr773Ser	missense_variant	20/33	1	NM_005406.3	P1
ROCK1	ENST00000635540.2	c.2318C>G	p.Thr773Ser	missense_variant, NMD_transcript_variant	20/34	5

Frequencies

GnomAD3 genomes AF: 0.00876 AC: 1332 AN: 152068 Hom.: 11 Cov.: 32

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

GnomAD3 exomes AF: 0.00932 AC: 2297 AN: 246472 Hom.: 15 AF XY: 0.00904 AC XY: 1205 AN XY: 133326

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 SAS exome AF: 0.00408

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.: 30 AF XY: 0.0120 AC XY: 8713 AN XY: 724564

Gnomad4 AFR exome AF: 0.00145

Gnomad4 AMR exome AF: 0.00277

Gnomad4 ASJ exome AF: 0.00636

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00414

Gnomad4 FIN exome AF: 0.0172

Gnomad4 NFE exome AF: 0.0139

Gnomad4 OTH exome AF: 0.0109

GnomAD4 genome AF: 0.00875 AC: 1331 AN: 152186 Hom.: 11 Cov.: 32 AF XY: 0.00829 AC XY: 617 AN XY: 74408

Gnomad4 AFR AF: 0.00265

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.00722

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.0147

Gnomad4 NFE AF: 0.0136

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00977 Hom.: 10

Bravo AF: 0.00768

TwinsUK AF: 0.0148 AC: 55

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.0130 AC: 112

ExAC AF: 0.00942 AC: 1144

Asia WGS AF: 0.00145 AC: 6 AN: 3470

EpiCase AF: 0.0119

EpiControl AF: 0.0117

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ROCK1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jun 15, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.11
Sift	Benign	0.42	T
Sift4G	Benign	0.75	T
Polyphen		0.0010	B
Vest4		0.068
MutPred		0.095		Gain of phosphorylation at T773 (P = 0.0751);
MVP		0.31
MPC		0.41
ClinPred		0.0099	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.074
gMVP		0.046

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

Other links and lift over

dbSNP: rs45562542; hg19: chr18-18564483;