18-21049812-T-C

Variant names:

• chr18-21049812-T-C
• rs1415552718
• NM_005406.3:c.244A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005406.3(ROCK1):​c.244A>G​(p.Ile82Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,238 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 (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ROCK1 NM_005406.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.88

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.779

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROCK1	NM_005406.3	c.244A>G	p.Ile82Val	missense_variant	Exon 3 of 33	ENST00000399799.3	NP_005397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROCK1	ENST00000399799.3	c.244A>G	p.Ile82Val	missense_variant	Exon 3 of 33	1	NM_005406.3	ENSP00000382697.1
ROCK1	ENST00000635540.2	n.244A>G		non_coding_transcript_exon_variant	Exon 3 of 34	5		ENSP00000489185.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 27

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74380

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.244A>G (p.I82V) alteration is located in exon 3 (coding exon 3) of the ROCK1 gene. This alteration results from a A to G substitution at nucleotide position 244, causing the isoleucine (I) at amino acid position 82 to be replaced by a valine (V). 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	0.85
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.10	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.9	L
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.90	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.64
MutPred		0.81		Gain of methylation at R84 (P = 0.11);
MVP		0.62
MPC		2.1
ClinPred		0.89	D
GERP RS		5.5
Varity_R		0.60
gMVP		0.74

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: rs1415552718; hg19: chr18-18629773;