NM_001039469.3:c.581T>C

Variant names:

• chr11-63899923-T-C
• rs1940729976
• NM_001039469.3:c.581T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 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. 13/22 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
• 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: Likely_pathogenic. The variant received 6 ACMG points.

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

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.581T>C	p.Phe194Ser	missense	Exon 8 of 19	NP_001034558.2	Q7KZI7-1
	MARK2	NM_017490.4		c.482T>C	p.Phe161Ser	missense	Exon 8 of 18	NP_059672.2	Q7KZI7-14
	MARK2	NM_004954.5		c.581T>C	p.Phe194Ser	missense	Exon 8 of 17	NP_004945.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MARK2	ENST00000402010.8	TSL:1 MANE Select	c.581T>C	p.Phe194Ser	missense	Exon 8 of 19	ENSP00000385751.2	Q7KZI7-1
	MARK2	ENST00000513765.7	TSL:1	c.581T>C	p.Phe194Ser	missense	Exon 8 of 18	ENSP00000421075.3	Q7KZI7-8
	MARK2	ENST00000425897.3	TSL:1	c.581T>C	p.Phe194Ser	missense	Exon 8 of 17	ENSP00000415494.3	E7ETY4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Autism spectrum disorder (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Pathogenic	4.7	H
PhyloP100		8.0
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.91		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
Mutation Taster		=14/86	disease causing

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

Other links and lift over

dbSNP: rs1940729976; hg19: chr11-63667395;