chr18-20984384-C-T

Variant names:

• chr18-20984384-C-T
• NM_005406.3:c.2456G>A

Variant summary

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

The NM_005406.3(ROCK1):​c.2456G>A​(p.Arg819Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,456,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ROCK1 NM_005406.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.49
• Publications: 0 publications found

Genes affected

ROCK1 (HGNC:10251): (Rho associated coiled-coil containing protein kinase 1) This gene encodes a protein serine/threonine kinase that is activated when bound to the GTP-bound form of Rho. The small GTPase Rho regulates formation of focal adhesions and stress fibers of fibroblasts, as well as adhesion and aggregation of platelets and lymphocytes by shuttling between the inactive GDP-bound form and the active GTP-bound form. Rho is also essential in cytokinesis and plays a role in transcriptional activation by serum response factor. This protein, a downstream effector of Rho, phosphorylates and activates LIM kinase, which in turn, phosphorylates cofilin, inhibiting its actin-depolymerizing activity. A pseudogene, related to this gene, is also located on chromosome 18. [provided by RefSeq, Aug 2015]

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=0.17628783).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005406.3. 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
	ROCK1	NM_005406.3	MANE Select	c.2456G>A	p.Arg819Lys	missense	Exon 20 of 33	NP_005397.1	Q13464

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROCK1	ENST00000399799.3	TSL:1 MANE Select	c.2456G>A	p.Arg819Lys	missense	Exon 20 of 33	ENSP00000382697.1	Q13464
	ROCK1	ENST00000635540.2	TSL:5	n.2456G>A		non_coding_transcript_exon	Exon 20 of 34	ENSP00000489185.1	A0A0U1RQV4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456620 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 724718

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000301 AC: 1 AN: 33250

American (AMR) AF: 0.00 AC: 0 AN: 44006

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39576

South Asian (SAS) AF: 0.00 AC: 0 AN: 85526

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52830

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5012

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110178

Other (OTH) AF: 0.00 AC: 0 AN: 60172

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.083
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		5.5
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.16
Sift	Benign	0.44	T
Sift4G	Benign	0.48	T
Polyphen		0.021	B
Vest4		0.39
MutPred		0.23		Gain of ubiquitination at R819 (P = 0.0121)
MVP		0.56
MPC		0.51
ClinPred		0.85	D
GERP RS		4.9
Varity_R		0.36
gMVP		0.27
Mutation Taster		=74/26	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

hg19: chr18-18564345;