18-21039464-A-G

Position:

• chr18-21039464-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005406.3(ROCK1):​c.1051+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00414 in 1,592,280 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (21 hom.)
• Consequence: ROCK1 NM_005406.3 splice_region, intron
• Scores: Splicing: ADA: 0.0003838
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.20

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 18-21039464-A-G is Benign according to our data. Variant chr18-21039464-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 784748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 407 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ROCK1	NM_005406.3	c.1051+8T>C		splice_region_variant, intron_variant		ENST00000399799.3	NP_005397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ROCK1	ENST00000399799.3	c.1051+8T>C		splice_region_variant, intron_variant		1	NM_005406.3	ENSP00000382697.1
ROCK1	ENST00000635540.2	n.1051+8T>C		splice_region_variant, intron_variant		5		ENSP00000489185.1

Frequencies

GnomAD3 genomes AF: 0.00268 AC: 408 AN: 152158 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00469

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00257 AC: 605 AN: 235196 Hom.: 8 AF XY: 0.00279 AC XY: 355 AN XY: 127366

Gnomad AFR exome AF: 0.000756

Gnomad AMR exome AF: 0.000786

Gnomad ASJ exome AF: 0.000107

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00182

Gnomad FIN exome AF: 0.000610

Gnomad NFE exome AF: 0.00449

Gnomad OTH exome AF: 0.00304

GnomAD4 exome AF: 0.00429 AC: 6179 AN: 1440004 Hom.: 21 Cov.: 29 AF XY: 0.00426 AC XY: 3053 AN XY: 716880

Gnomad4 AFR exome AF: 0.000785

Gnomad4 AMR exome AF: 0.000873

Gnomad4 ASJ exome AF: 0.0000785

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00164

Gnomad4 FIN exome AF: 0.000809

Gnomad4 NFE exome AF: 0.00521

Gnomad4 OTH exome AF: 0.00320

GnomAD4 genome AF: 0.00267 AC: 407 AN: 152276 Hom.: 2 Cov.: 32 AF XY: 0.00242 AC XY: 180 AN XY: 74470

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00467

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00350 Hom.: 1

Bravo AF: 0.00242

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	ROCK1: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 21, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.24
DANN	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00038
dbscSNV1_RF	Benign	0.018
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: rs111381414; hg19: chr18-18619425;