11-63898673-GGA-AGG

Variant names:

• chr11-63898673-GGT-AGG
• NM_001039469.3:c.403_403+2delGGTinsAGG
• MARK2 p.Gly135Arg

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_001039469.3(MARK2):​c.403_403+2delGGTinsAGG​(p.Gly135Arg) variant causes a splice donor, missense, splice region, intron change involving the alteration of a 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 MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. 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 Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MARK2 NM_001039469.3 splice_donor, missense, splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.70
• Publications: 0 publications found

Genes affected

MARK2 (HGNC:3332): (microtubule affinity regulating kinase 2) This gene encodes a member of the Par-1 family of serine/threonine protein kinases. The protein is an important regulator of cell polarity in epithelial and neuronal cells, and also controls the stability of microtubules through phosphorylation and inactivation of several microtubule-associating proteins. The protein localizes to cell membranes. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2009]

ACMG classification

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

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.027883397 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.5, offset of 4, new splice context is: gagGTgtgg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039469.3. 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
	MARK2	NM_001039469.3	MANE Select	c.403_403+2delGGTinsAGG	p.Gly135Arg	splice_donor missense splice_region intron	N/A	NP_001034558.2	Q7KZI7-1
	MARK2	NM_017490.4		c.304_304+2delGGTinsAGG	p.Gly102Arg	splice_donor missense splice_region intron	N/A	NP_059672.2	Q7KZI7-14
	MARK2	NM_004954.5		c.403_403+2delGGTinsAGG	p.Gly135Arg	splice_donor missense splice_region intron	N/A	NP_004945.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MARK2	ENST00000402010.8	TSL:1 MANE Select	c.403_403+2delGGTinsAGG	p.Gly135Arg	splice_donor missense splice_region intron	N/A	ENSP00000385751.2	Q7KZI7-1
	MARK2	ENST00000513765.7	TSL:1	c.403_403+2delGGTinsAGG	p.Gly135Arg	splice_donor missense splice_region intron	N/A	ENSP00000421075.3	Q7KZI7-8
	MARK2	ENST00000425897.3	TSL:1	c.403_403+2delGGTinsAGG	p.Gly135Arg	splice_donor missense splice_region intron	N/A	ENSP00000415494.3	E7ETY4

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.7

Splicing

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.

Other links and lift over

hg19: chr11-63666145;