2-11201391-C-G

Variant names:

• chr2-11201391-C-G
• rs200468857
• NM_004850.5:c.2642G>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004850.5(ROCK2):​c.2642G>C​(p.Arg881Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000715 in 1,608,946 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 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000072 (0 hom.)
• Consequence: ROCK2 NM_004850.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.88

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]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18317726).
• BS2: High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROCK2	NM_004850.5	c.2642G>C	p.Arg881Thr	missense_variant	Exon 22 of 33	ENST00000315872.11	NP_004841.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROCK2	ENST00000315872.11	c.2642G>C	p.Arg881Thr	missense_variant	Exon 22 of 33	1	NM_004850.5	ENSP00000317985.6

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000322 AC: 8 AN: 248654 AF XY: 0.0000296

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000532

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000721 AC: 105 AN: 1456800 Hom.: 0 Cov.: 28 AF XY: 0.0000717 AC XY: 52 AN XY: 725090

Gnomad4 AFR exome AF: 0.0000599 AC: 2 AN: 33394

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44682

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26092

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39636

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86132

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53046

Gnomad4 NFE exome AF: 0.0000921 AC: 102 AN: 1107810

Gnomad4 Remaining exome AF: 0.0000166 AC: 1 AN: 60252

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74334

Gnomad4 AFR AF: 0.0000241 AC: 0.0000241348 AN: 0.0000241348

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000132 AC: 0.000132291 AN: 0.000132291

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2642G>C (p.R881T) alteration is located in exon 22 (coding exon 22) of the ROCK2 gene. This alteration results from a G to C substitution at nucleotide position 2642, causing the arginine (R) at amino acid position 881 to be replaced by a threonine (T). 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	Pathogenic	0.76
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.17	T;.;.
Eigen	Benign	-0.049
Eigen_PC	Benign	0.044
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.0	M;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.4	N;.;N
REVEL	Benign	0.15
Sift	Benign	0.065	T;.;T
Sift4G	Benign	0.10	T;T;T
Polyphen		0.43	B;.;.
Vest4		0.57
MVP		0.33
MPC		1.5
ClinPred		0.10	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.26
Mutation Taster		=66/34	polymorphism

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: rs200468857; hg19: chr2-11341517;