rs1554191995

Positions:

• chr6-113860194-CCGAGGCGGGCGCGGCCT-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_002356.7(MARCKS):​c.616_632del​(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. 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

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 521555.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MARCKS	NM_002356.7	c.616_632del	p.Glu206ArgfsTer130	frameshift_variant	2/2	ENST00000612661.2	NP_002347.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MARCKS	ENST00000612661.2	c.616_632del	p.Glu206ArgfsTer130	frameshift_variant	2/2	1	NM_002356.7	ENSP00000478061	P1

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 04, 2020

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 v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554191995; hg19: chr6-114181370;