rs1554191995

Variant names:

• chr6-113860194-CCGAGGCGGGCGCGGCCT-C
• rs1554191995
• NM_002356.7:c.616_632delGAGGCGGGCGCGGCCTC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP5_Moderate

The NM_002356.7(MARCKS):​c.616_632delGAGGCGGGCGCGGCCTC​(p.Glu206ArgfsTer130) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MARCKS NM_002356.7 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.97
• Publications: 0 publications found

Genes affected

MARCKS (HGNC:6759): (myristoylated alanine rich protein kinase C substrate) The protein encoded by this gene is a substrate for protein kinase C. It is localized to the plasma membrane and is an actin filament crosslinking protein. Phosphorylation by protein kinase C or binding to calcium-calmodulin inhibits its association with actin and with the plasma membrane, leading to its presence in the cytoplasm. The protein is thought to be involved in cell motility, phagocytosis, membrane trafficking and mitogenesis. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP5: Variant 6-113860194-CCGAGGCGGGCGCGGCCT-C is Pathogenic according to our data. Variant chr6-113860194-CCGAGGCGGGCGCGGCCT-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 521555.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002356.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MARCKS	NM_002356.7	MANE Select	c.616_632delGAGGCGGGCGCGGCCTC	p.Glu206ArgfsTer130	frameshift	Exon 2 of 2	NP_002347.5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MARCKS	ENST00000612661.2	TSL:1 MANE Select	c.616_632delGAGGCGGGCGCGGCCTC	p.Glu206ArgfsTer130	frameshift	Exon 2 of 2	ENSP00000478061.1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Pathogenic:1

Jun 04, 2020

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration results in an elongated protein:_x000D_ _x000D_ The c.616_632del17 (p.E206Rfs*130) alteration, located in coding exon 2 of the MARCKS gene, results from a deletion of 17 nucleotides from position 616 to 632, causing a translational frameshift with a predicted alternate stop codon. Frameshifts are typically deleterious in nature; however, this frameshift occurs at the 3' terminus of MARCKS, is not expected to trigger nonsense-mediated mRNA decay, and an altered mutant protein could still be expressed (Maquat, 2004). This frameshift changes the remaining 127 amino acids of the protein and elongates the protein by 2 amino acids. The exact functional impact of these altered amino acids is unknown at this time. This alteration is located in a functionally important protein domain:_x000D_ _x000D_ The p.E206RFS*130 amino acid starts in an observed calmodulin binding region, which is known be required for MARCKS protein function (Naim, 1992; Hartwig, 1992; Gallant, 2005). Based on the available evidence, this alteration is classified as likely pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.0

Splicing

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

Other links and lift over

dbSNP: rs1554191995; hg19: chr6-114181370;