Genetic Variant NM_001242957.3:c.1943G>C (chr6-10764456-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001242957.3(MAK):c.1943G>C(p.Arg648Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. R648W) 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: 3.94

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001242957.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAK	NM_001242957.3	MANE Select	c.1943G>C	p.Arg648Pro	missense	Exon 15 of 15	NP_001229886.1	P20794-2
MAK	NM_005906.6		c.1868G>C	p.Arg623Pro	missense	Exon 14 of 14	NP_005897.1	A0A140VK28
MAK	NM_001242385.2		c.1748G>C	p.Arg583Pro	missense	Exon 13 of 13	NP_001229314.1	P20794-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAK	ENST00000354489.7	TSL:5 MANE Select	c.1943G>C	p.Arg648Pro	missense	Exon 15 of 15	ENSP00000346484.3	P20794-2
MAK	ENST00000474039.5	TSL:1	c.1868G>C	p.Arg623Pro	missense	Exon 14 of 14	ENSP00000476067.1	P20794-1
MAK	ENST00000536370.6	TSL:1	c.1748G>C	p.Arg583Pro	missense	Exon 13 of 13	ENSP00000442221.2	P20794-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251062

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.17

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.52

MetaSVM

Uncertain

0.21

MutationAssessor

Uncertain

2.3

PhyloP100

3.9

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.62

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.95

Vest4

0.64

MutPred

0.41

Loss of MoRF binding (P = 2e-04)

MVP

0.88

MPC

0.82

ClinPred

0.99

GERP RS

5.8

Varity_R

0.85

gMVP

0.71

Mutation Taster

=62/38

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over