2-11197675-G-A

Variant names:

• chr2-11197675-G-A
• rs1383664600
• NM_004850.5:c.3130C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_004850.5(ROCK2):​c.3130C>T​(p.Arg1044*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000694 in 1,440,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ROCK2 NM_004850.5 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.37
• Publications: 0 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

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.3130C>T	p.Arg1044*	stop_gained	Exon 26 of 33	NP_004841.2
	ROCK2	NM_001321643.2		c.2872C>T	p.Arg958*	stop_gained	Exon 26 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.3130C>T	p.Arg1044*	stop_gained	Exon 26 of 33	ENSP00000317985.6	O75116
	ROCK2	ENST00000401753.5	TSL:1	c.2401C>T	p.Arg801*	stop_gained	Exon 22 of 29	ENSP00000385509.1	E9PF63
	ROCK2	ENST00000944889.1		c.3130C>T	p.Arg1044*	stop_gained	Exon 26 of 34	ENSP00000614948.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000419 AC: 1 AN: 238894 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000103

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1440898 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 715882

African (AFR) AF: 0.00 AC: 0 AN: 32966

American (AMR) AF: 0.00 AC: 0 AN: 43110

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25588

East Asian (EAS) AF: 0.00 AC: 0 AN: 39048

South Asian (SAS) AF: 0.00 AC: 0 AN: 80784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101936

Other (OTH) AF: 0.0000168 AC: 1 AN: 59516

GnomAD4 genome Cov.: 33

Alfa AF: 0.000111 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Non-immune hydrops fetalis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		5.4
Vest4		0.99
GERP RS		5.5
Mutation Taster		=5/195	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1383664600; hg19: chr2-11337801; COSMIC: COSV59956820; COSMIC: COSV59956820;