Genetic Variant ROCK2:p.Arg1377Gln (chr2-11192180-CC-TT) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_004850.5(ROCK2):c.4130_4131delGGinsAA (p.Arg1377Gln) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R1377Q: Uncertain_significance (ClinVar VariationId 2490312, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

Frequency

Genomes: not found (cov: 32)

Consequence

ROCK2
NM_004850.5 missense

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.96

Publications

0 publications found

Variant links:

Genes affected

ROCK2 (HGNC:10252): (Rho associated coiled-coil containing protein kinase 2) The protein encoded by this gene is a serine/threonine kinase that regulates cytokinesis, smooth muscle contraction, the formation of actin stress fibers and focal adhesions, and the activation of the c-fos serum response element. This protein, which is an isozyme of ROCK1 is a target for the small GTPase Rho. [provided by RefSeq, Jul 2008]

ROCK2 Gene-Disease associations (from GenCC):

congenital heart disease
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, ClinGen

ROCK2 links:

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new If you want to explore the variant's impact on the transcript NM_004850.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Show applied only (1)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_004850.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ROCK2 NM_004850.5	MANE Select	c.4130_4131delGGinsAA p.Arg1377Gln	missense	N/A	Prot: NP_004841.2
	ROCK2 NM_001321643.2		c.3872_3873delGGinsAA p.Arg1291Gln	missense	N/A	Prot: NP_001308572.1

ROCK2 NM_004850.5

MANE Select

HGVSc / HGVSpc.4130_4131delGGinsAAp.Arg1377Gln

Exon rankN/A

missense

Prot: NP_004841.2

ROCK2 NM_001321643.2

HGVSc / HGVSpc.3872_3873delGGinsAAp.Arg1291Gln

Exon rankN/A

missense

Prot: NP_001308572.1

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
ROCK2 ENST00000315872.11	TSL:1MANE Select	c.4130_4131delGGinsAA p.Arg1377Gln	missense	N/A	Prot: ENSP00000317985.6 UniProt: O75116
ROCK2 ENST00000401753.5	TSL:1	c.3401_3402delGGinsAA p.Arg1134Gln	missense	N/A	Prot: ENSP00000385509.1 UniProt: E9PF63
ROCK2 ENST00000944889.1		c.4307_4308delGGinsAA p.Arg1436Gln	missense	N/A	Prot: ENSP00000614948.1 UniProt: A0ACI8UDE5

ROCK2 ENST00000315872.11

TSL:1MANE Select

HGVSc / HGVSpc.4130_4131delGGinsAAp.Arg1377Gln

Exon rankN/A

missense

Prot: ENSP00000317985.6UniProt: O75116

ROCK2 ENST00000401753.5

TSL:1

HGVSc / HGVSpc.3401_3402delGGinsAAp.Arg1134Gln

Exon rankN/A

missense

Prot: ENSP00000385509.1UniProt: E9PF63

ROCK2 ENST00000944889.1

HGVSc / HGVSpc.4307_4308delGGinsAAp.Arg1436Gln

Exon rankN/A

missense

Prot: ENSP00000614948.1UniProt: A0ACI8UDE5

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	5.0

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence