Genetic Variant MAK:p.Gln240Lys (chr6-10802005-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_001242957.3(MAK):c.718C>A(p.Gln240Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MAK
NM_001242957.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.30

Variant links:

Genes affected

MAK (HGNC:6816): (male germ cell associated kinase) The product of this gene is a serine/threonine protein kinase related to kinases involved in cell cycle regulation. Studies of the mouse and rat homologs have localized the kinase to the chromosomes during meiosis in spermatogenesis, specifically to the synaptonemal complex that exists while homologous chromosomes are paired. Mutations in this gene have been associated with ciliary defects resulting in retinitis pigmentosa 62. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

MAK links:

TMEM14B (HGNC:21384): (transmembrane protein 14B) Enables identical protein binding activity. Involved in cerebral cortex development; neural precursor cell proliferation; and regulation of G1/S transition of mitotic cell cycle. Predicted to be integral component of membrane. Predicted to be active in mitochondrial inner membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM14B links:

ENSG00000272162 (HGNC:):

ENSG00000272162 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a domain Protein kinase (size 280) in uniprot entity MAK_HUMAN there are 19 pathogenic changes around while only 1 benign (95%) in NM_001242957.3

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3805849).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAK	NM_001242957.3 link	c.718C>A	p.Gln240Lys	missense_variant	Exon 8 of 15	ENST00000354489.7	NP_001229886.1	P20794-2F8VBW7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAK	ENST00000354489.7 link	c.718C>A	p.Gln240Lys	missense_variant	Exon 8 of 15	5	NM_001242957.3	ENSP00000346484.3		P20794-2
ENSG00000272162	ENST00000480294.1 link	n.100+52307G>T		intron_variant	Intron 3 of 18	2		ENSP00000417929.1		F8WBI7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461814

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727218

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.022

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;T;.;.;.

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.95

.;D;D;D;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.38

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.28

N;N;N;N;.

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.8

D;.;D;D;D

REVEL

Benign

0.23

Sift

Benign

0.049

D;.;D;T;T

Sift4G

Uncertain

0.048

D;D;T;T;T

Polyphen

0.53

P;P;.;.;.

Vest4

0.43

MutPred

0.48

Gain of methylation at Q240 (P = 4e-04);Gain of methylation at Q240 (P = 4e-04);Gain of methylation at Q240 (P = 4e-04);Gain of methylation at Q240 (P = 4e-04);Gain of methylation at Q240 (P = 4e-04);

MVP

0.58

MPC

0.68

ClinPred

0.93

GERP RS

5.7

Varity_R

0.67

gMVP

0.74

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over