ROCK2 p.Arg1377Gln

Variant names:

• chr2-11192181-C-T
• rs1483703733
• NM_004850.5:c.4130G>A
• ROCK2 p.Arg1377Gln

Your query was ambiguous. Multiple possible variants found:

• chr2-11192181-C-T
• chr2-11192180-CC-TT

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-5 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -5 classification points (ACMG Germline Pathogenicity v2019). BS2BP4

The NM_004850.5(ROCK2):c.4130G>A (p.Arg1377Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000807 (AC=13) in the gnomAD database across 1,610,728 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000208. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: ROCK2 NM_004850.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.96
• Publications: 1 publications found

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: PanelApp Australia, ClinGen

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Supporting).
	BS2Observed in healthy adult		Pure AD gene with cumulative gnomAD AC ≥5 — observed in healthy adults (BS2); GnomAD homozygous count = 0.; Cumulative gnomAD AC = 13 (pure AD gene, not AR).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_004850.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ROCK2 NM_004850.5	MANE Select	c.4130G>A p.Arg1377Gln	missense	Exon 32 of 33	Prot: NP_004841.2
	ROCK2 NM_001321643.2		c.3872G>A p.Arg1291Gln	missense	Exon 32 of 33	Prot: NP_001308572.1

ROCK2 NM_004850.5

MANE Select

HGVSc / HGVSpc.4130G>Ap.Arg1377Gln

Exon rankExon 32 of 33

missense

Prot: NP_004841.2

ROCK2 NM_001321643.2

HGVSc / HGVSpc.3872G>Ap.Arg1291Gln

Exon rankExon 32 of 33

missense

Prot: NP_001308572.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ROCK2 ENST00000315872.11	TSL:1MANE Select	c.4130G>A p.Arg1377Gln	missense	Exon 32 of 33	Prot: ENSP00000317985.6 UniProt:
	ROCK2 ENST00000401753.5	TSL:1	c.3401G>A p.Arg1134Gln	missense	Exon 28 of 29	Prot: ENSP00000385509.1 UniProt:
	ROCK2 ENST00000944889.1		c.4307G>A p.Arg1436Gln	missense	Exon 33 of 34	Prot: ENSP00000614948.1 UniProt:

ROCK2 ENST00000315872.11

TSL:1MANE Select

HGVSc / HGVSpc.4130G>Ap.Arg1377Gln

Exon rankExon 32 of 33

missense

Prot: ENSP00000317985.6UniProt: O75116

ROCK2 ENST00000401753.5

TSL:1

HGVSc / HGVSpc.3401G>Ap.Arg1134Gln

Exon rankExon 28 of 29

missense

Prot: ENSP00000385509.1UniProt: E9PF63

ROCK2 ENST00000944889.1

HGVSc / HGVSpc.4307G>Ap.Arg1436Gln

Exon rankExon 33 of 34

missense

Prot: ENSP00000614948.1UniProt: A0ACI8UDE5

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000132	AC:2	Hom:0	AN:151536	Cov:32
GnomAD2 exomes	AF: 0.0000121	AC:3	Hom:	AN:248086	Cov:
GnomAD4 exome	AF: 0.00000754	AC:11	Hom:0	AN:1459192	Cov:32
GnomAD4 genome	AF: 0.0000132	AC:2	Hom:0	AN:151536	Cov:32
TOPMed (Bravo) Warning	AF: 0.0000113	AC:3	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000636	AC:3	Hom:0	AN:47206	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.00	0	102918	0.0000164	3	183474

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	25
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.067	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.91	D
FuncVEP CTI	Benign	0.040
GPN-Star LLR	N/A	-8.9
GPN-Star score	N/A	8.9
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.95	T
Mutation Taster	N/A	71/29	polymorphism
MutationAssessor	Benign	0.0	N
PhyloP100	Uncertain	5.0
popEVE	Benign	-3.4
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.13	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Benign	0.27
Sift	Benign	0.34	T
Sift4G	Benign	0.58	T
Varity_R	N/A	0.12
VESM-3B	Benign	-5.7

Showing 30 of 30 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.020
SpliceAI score (max)	Benign	0.020	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1483703733;

hg19: chr2-11332307;

COSMIC: COSV59955850;

COSMIC: COSV59955850;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar