chr11-63899923-T-C

Position:

• chr11-63899923-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001039469.3(MARK2):​c.581T>C​(p.Phe194Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MARK2 NM_001039469.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 8.02

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MARK2	NM_001039469.3	c.581T>C	p.Phe194Ser	missense_variant	8/19	ENST00000402010.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MARK2	ENST00000402010.8	c.581T>C	p.Phe194Ser	missense_variant	8/19	1	NM_001039469.3	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autism spectrum disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Department of Medical Genetics, Capital Institute of Pediatrics

Jul 03, 2024

PM2_Supporting+PS2+PP3 -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

research

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Apr 09, 2020

ACMG codes:PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;T;.;.;.;.;.;.;.;.;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;D;D;D;.
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Pathogenic	4.7	H;.;H;H;H;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-7.7	D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;.;.;D;.;.;D
Vest4		0.99
MutPred		0.91		Gain of glycosylation at F194 (P = 0.0225);.;Gain of glycosylation at F194 (P = 0.0225);Gain of glycosylation at F194 (P = 0.0225);Gain of glycosylation at F194 (P = 0.0225);Gain of glycosylation at F194 (P = 0.0225);.;.;.;.;.;
MVP		0.93
MPC		3.6
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.97
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs1940729976; hg19: chr11-63667395;