rs2663698

Variant names:

• chr18-20954846-A-G
• rs2663698
• NM_005406.3:c.3790T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_005406.3(ROCK1):​c.3790T>C​(p.Cys1264Arg) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ROCK1 NM_005406.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.25
• Publications: 5 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985

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.3790T>C	p.Cys1264Arg	missense	Exon 31 of 33	NP_005397.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROCK1	ENST00000399799.3	TSL:1 MANE Select	c.3790T>C	p.Cys1264Arg	missense	Exon 31 of 33	ENSP00000382697.1
	ROCK1	ENST00000578051.1	TSL:2	c.25T>C	p.Cys9Arg	missense	Exon 1 of 2	ENSP00000462004.1
	ROCK1	ENST00000635540.2	TSL:5	n.*425T>C		non_coding_transcript_exon	Exon 32 of 34	ENSP00000489185.1

Frequencies

GnomAD3 genomes AF: 0.000122 AC: 18 AN: 147984 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000250

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000820

Gnomad SAS AF: 0.000217

Gnomad FIN AF: 0.000293

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000135

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1460936 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726782

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.00 AC: 0 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111444

Other (OTH) AF: 0.00 AC: 0 AN: 60334

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000128 AC: 19 AN: 148092 Hom.: 0 Cov.: 33 AF XY: 0.000166 AC XY: 12 AN XY: 72352

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000250 AC: 1 AN: 40052

American (AMR) AF: 0.00 AC: 0 AN: 14954

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.00103 AC: 5 AN: 4866

South Asian (SAS) AF: 0.000217 AC: 1 AN: 4600

European-Finnish (FIN) AF: 0.000293 AC: 3 AN: 10224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.000135 AC: 9 AN: 66722

Other (OTH) AF: 0.00 AC: 0 AN: 2054

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000429 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	32
DANN	Benign	0.93
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-9.8	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.85		Gain of disorder (P = 0.0207)
MVP		0.98
MPC		4.9
ClinPred		1.0	D
GERP RS		5.6
PromoterAI		0.18	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.87
Mutation Taster		=7/93	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2663698; hg19: chr18-18534807; COSMIC: COSV67695441; COSMIC: COSV67695441;