18-21039464-A-G

Variant names:

• chr18-21039464-A-G
• rs111381414
• NM_005406.3:c.1051+8T>C

Variant summary

Our verdict is Benign. The variant received -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
• 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: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 784748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 407 AD gene.

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.1051+8T>C		splice_region intron	N/A	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.1051+8T>C		splice_region intron	N/A	ENSP00000382697.1	Q13464
	ROCK1	ENST00000635540.2	TSL:5	n.1051+8T>C		splice_region intron	N/A	ENSP00000489185.1	A0A0U1RQV4

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

GnomAD2 exomes AF: 0.00257 AC: 605 AN: 235196 AF XY: 0.00279

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 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

African (AFR) AF: 0.000785 AC: 25 AN: 31848

American (AMR) AF: 0.000873 AC: 35 AN: 40080

Ashkenazi Jewish (ASJ) AF: 0.0000785 AC: 2 AN: 25470

East Asian (EAS) AF: 0.00 AC: 0 AN: 39568

South Asian (SAS) AF: 0.00164 AC: 136 AN: 82686

European-Finnish (FIN) AF: 0.000809 AC: 43 AN: 53122

Middle Eastern (MID) AF: 0.000897 AC: 5 AN: 5572

European-Non Finnish (NFE) AF: 0.00521 AC: 5743 AN: 1102334

Other (OTH) AF: 0.00320 AC: 190 AN: 59324

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

African (AFR) AF: 0.00120 AC: 50 AN: 41568

American (AMR) AF: 0.00105 AC: 16 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4820

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00467 AC: 318 AN: 68022

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.00350 Hom.: 1

Bravo AF: 0.00242

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.24
DANN	Benign	0.53
PhyloP100		-2.2
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs111381414; hg19: chr18-18619425;