18-20969146-C-G

Variant names:

• chr18-20969146-C-G
• rs747013639
• NM_005406.3:c.2883G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005406.3(ROCK1):​c.2883G>C​(p.Glu961Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,449,558 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: ROCK1 NM_005406.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.412
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.098704904).

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.2883G>C	p.Glu961Asp	missense	Exon 24 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.2883G>C	p.Glu961Asp	missense	Exon 24 of 33	ENSP00000382697.1	Q13464
	ROCK1	ENST00000584875.1	TSL:2	n.209G>C		non_coding_transcript_exon	Exon 1 of 2
	ROCK1	ENST00000635540.2	TSL:5	n.2883G>C		non_coding_transcript_exon	Exon 24 of 34	ENSP00000489185.1	A0A0U1RQV4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000285 AC: 7 AN: 245574 AF XY: 0.0000375

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000620

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000124 AC: 18 AN: 1449558 Hom.: 0 Cov.: 28 AF XY: 0.0000111 AC XY: 8 AN XY: 721836

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

African (AFR) AF: 0.00 AC: 0 AN: 33362

American (AMR) AF: 0.00 AC: 0 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39572

South Asian (SAS) AF: 0.00 AC: 0 AN: 86002

European-Finnish (FIN) AF: 0.0000218 AC: 1 AN: 45884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1108144

Other (OTH) AF: 0.00 AC: 0 AN: 60170

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000116174), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000285 Hom.: 0

ExAC AF: 0.0000577 AC: 7

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.099	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.41
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.059
Sift	Benign	0.40	T
Sift4G	Benign	0.34	T
Polyphen		0.031	B
Vest4		0.17
MutPred		0.57		Loss of stability (P = 0.1649)
MVP		0.30
MPC		0.46
ClinPred		0.060	T
GERP RS		0.16
Varity_R		0.15
gMVP		0.16
Mutation Taster		=64/36	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

dbSNP: rs747013639; hg19: chr18-18549107;