2-11201391-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004850.5(ROCK2):​c.2642G>A​(p.Arg881Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000311 in 1,608,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R881T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ROCK2 NM_004850.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.88
• 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: ClinGen, PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08068541).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004850.5. 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
	ROCK2	NM_004850.5	MANE Select	c.2642G>A	p.Arg881Lys	missense	Exon 22 of 33	NP_004841.2
	ROCK2	NM_001321643.2		c.2384G>A	p.Arg795Lys	missense	Exon 22 of 33	NP_001308572.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROCK2	ENST00000315872.11	TSL:1 MANE Select	c.2642G>A	p.Arg881Lys	missense	Exon 22 of 33	ENSP00000317985.6	O75116
	ROCK2	ENST00000401753.5	TSL:1	c.1913G>A	p.Arg638Lys	missense	Exon 18 of 29	ENSP00000385509.1	E9PF63
	ROCK2	ENST00000944889.1		c.2642G>A	p.Arg881Lys	missense	Exon 22 of 34	ENSP00000614948.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000804 AC: 2 AN: 248654 AF XY: 0.00000741

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000936

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456800 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 725090

African (AFR) AF: 0.00 AC: 0 AN: 33394

American (AMR) AF: 0.00 AC: 0 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.00 AC: 0 AN: 86132

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 53046

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107810

Other (OTH) AF: 0.00 AC: 0 AN: 60252

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74334

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000378 AC: 4 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.066	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.9
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.071
Sift	Benign	0.53	T
Sift4G	Benign	0.44	T
Polyphen		0.10	B
Vest4		0.088
MutPred		0.26		Gain of methylation at R881 (P = 0.0042)
MVP		0.45
MPC		0.95
ClinPred		0.18	T
GERP RS		3.6
Varity_R		0.15
gMVP		0.13
Mutation Taster		=86/14	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

Other links and lift over

dbSNP: rs200468857; hg19: chr2-11341517;