Genetic Variant NM_001242957.3:c.497G>C (chr6-10803886-C-G) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_001242957.3(MAK):c.497G>C(p.Arg166Pro) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R166C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

MAK
NM_001242957.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.70

Publications

3 publications found

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 was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-10803886-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 29784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAK	NM_001242957.3 link	c.497G>C	p.Arg166Pro	missense_variant	Exon 7 of 15	ENST00000354489.7	NP_001229886.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAK	ENST00000354489.7 link	c.497G>C	p.Arg166Pro	missense_variant	Exon 7 of 15	5	NM_001242957.3	ENSP00000346484.3
ENSG00000272162	ENST00000480294.1 link	n.100+54188C>G		intron_variant	Intron 3 of 18	2		ENSP00000417929.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

T;T;.;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

.;D;D;D;D

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Uncertain

0.18

MutationAssessor

Pathogenic

3.7

H;H;H;H;.

PhyloP100

7.7

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-6.9

D;.;D;D;D

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

D;.;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;D;.;.;.

Vest4

0.97

MutPred

0.95

Loss of MoRF binding (P = 0.0236);Loss of MoRF binding (P = 0.0236);Loss of MoRF binding (P = 0.0236);Loss of MoRF binding (P = 0.0236);Loss of MoRF binding (P = 0.0236);

MVP

0.90

MPC

0.83

ClinPred

1.0

GERP RS

5.4

Varity_R

0.99

gMVP

0.96

Mutation Taster

=3/97

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over