2-11218994-G-T

Variant names:

• chr2-11218994-G-T
• rs2230774
• NM_004850.5:c.1292C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004850.5(ROCK2):​c.1292C>A​(p.Thr431Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.494 in 1,421,884 control chromosomes in the GnomAD database, including 179,796 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T431S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.46 (17221 hom., cov: 31)
  • Exomes 𝑓: 0.50 (162575 hom.)
• Consequence: ROCK2 NM_004850.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.02
• Publications: 72 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.8063906E-5).
• BP6: Variant 2-11218994-G-T is Benign according to our data. Variant chr2-11218994-G-T is described in ClinVar as Benign. ClinVar VariationId is 403387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.542 is higher than 0.05.

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.1292C>A	p.Thr431Asn	missense	Exon 10 of 33	NP_004841.2
	ROCK2	NM_001321643.2		c.1034C>A	p.Thr345Asn	missense	Exon 10 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.1292C>A	p.Thr431Asn	missense	Exon 10 of 33	ENSP00000317985.6	O75116
	ROCK2	ENST00000401753.5	TSL:1	c.563C>A	p.Thr188Asn	missense	Exon 6 of 29	ENSP00000385509.1	E9PF63
	ROCK2	ENST00000944889.1		c.1292C>A	p.Thr431Asn	missense	Exon 10 of 34	ENSP00000614948.1

Frequencies

GnomAD3 genomes AF: 0.456 AC: 69269 AN: 151766 Hom.: 17210 Cov.: 31

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.510

Gnomad AMR AF: 0.547

Gnomad ASJ AF: 0.457

Gnomad EAS AF: 0.402

Gnomad SAS AF: 0.461

Gnomad FIN AF: 0.545

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.546

Gnomad OTH AF: 0.457

GnomAD2 exomes AF: 0.486 AC: 104885 AN: 215796 AF XY: 0.487

Gnomad AFR exome AF: 0.239

Gnomad AMR exome AF: 0.538

Gnomad ASJ exome AF: 0.441

Gnomad EAS exome AF: 0.394

Gnomad FIN exome AF: 0.540

Gnomad NFE exome AF: 0.527

Gnomad OTH exome AF: 0.501

GnomAD4 exome AF: 0.498 AC: 632733 AN: 1270000 Hom.: 162575 Cov.: 21 AF XY: 0.498 AC XY: 316639 AN XY: 635842

African (AFR) AF: 0.221 AC: 6632 AN: 29972

American (AMR) AF: 0.541 AC: 18109 AN: 33462

Ashkenazi Jewish (ASJ) AF: 0.440 AC: 10038 AN: 22804

East Asian (EAS) AF: 0.398 AC: 14866 AN: 37358

South Asian (SAS) AF: 0.427 AC: 30374 AN: 71114

European-Finnish (FIN) AF: 0.546 AC: 27362 AN: 50140

Middle Eastern (MID) AF: 0.444 AC: 2234 AN: 5026

European-Non Finnish (NFE) AF: 0.515 AC: 497732 AN: 967070

Other (OTH) AF: 0.478 AC: 25386 AN: 53054

GnomAD4 genome AF: 0.456 AC: 69300 AN: 151884 Hom.: 17221 Cov.: 31 AF XY: 0.456 AC XY: 33863 AN XY: 74210

African (AFR) AF: 0.257 AC: 10657 AN: 41440

American (AMR) AF: 0.548 AC: 8351 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.457 AC: 1587 AN: 3472

East Asian (EAS) AF: 0.402 AC: 2076 AN: 5162

South Asian (SAS) AF: 0.461 AC: 2220 AN: 4812

European-Finnish (FIN) AF: 0.545 AC: 5733 AN: 10524

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.546 AC: 37100 AN: 67918

Other (OTH) AF: 0.458 AC: 967 AN: 2112

Alfa AF: 0.510 Hom.: 53775

Bravo AF: 0.444

TwinsUK AF: 0.537 AC: 1992

ALSPAC AF: 0.517 AC: 1993

ESP6500AA AF: 0.272 AC: 979

ESP6500EA AF: 0.530 AC: 4295

ExAC AF: 0.497 AC: 59968

Asia WGS AF: 0.416 AC: 1450 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	9.4
DANN	Benign	0.39
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.0094	N
LIST_S2	Benign	0.076	T
MetaRNN	Benign	0.000058	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.3	N
PhyloP100		1.0
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.30	N
REVEL	Benign	0.11
Sift	Benign	0.87	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.029
MPC		0.90
ClinPred		0.0035	T
GERP RS		4.4
Varity_R		0.032
gMVP		0.11
Mutation Taster		=93/7	polymorphism (auto)

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: rs2230774; hg19: chr2-11359120; COSMIC: COSV55075979; COSMIC: COSV55075979;