11-63895315-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001039469.3(MARK2):​c.211C>T​(p.Arg71*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MARK2
NM_001039469.3 stop_gained

Scores

3
3
1

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 0.634
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-63895315-C-T is Pathogenic according to our data. Variant chr11-63895315-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3253624.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MARK2NM_001039469.3 linkc.211C>T p.Arg71* stop_gained Exon 2 of 19 ENST00000402010.8 NP_001034558.2 Q7KZI7-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MARK2ENST00000402010.8 linkc.211C>T p.Arg71* stop_gained Exon 2 of 19 1 NM_001039469.3 ENSP00000385751.2 Q7KZI7-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461750
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727186
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Nov 15, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35982159, 35982160) -

Autism spectrum disorder Pathogenic:1
Jul 03, 2024
Department of Medical Genetics, Capital Institute of Pediatrics
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

PVS1+PM2_Supporting -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.61
D
BayesDel_noAF
Pathogenic
0.63
CADD
Pathogenic
38
DANN
Uncertain
1.0
Eigen
Pathogenic
0.69
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Uncertain
0.93
D
Vest4
0.94
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.17
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs868032104; hg19: chr11-63662787; API