dbSNP rs79544660: MAK:p.Ile572Thr (chr6-10770188-A-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001242957.3(MAK):c.1715T>C(p.Ile572Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00349 in 1,614,144 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0047 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 24 hom. )

Consequence

MAK
NM_001242957.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 1.05

Publications

8 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009576261).

BP6

Variant 6-10770188-A-G is Benign according to our data. Variant chr6-10770188-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194362.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00471 (717/152310) while in subpopulation AFR AF = 0.00825 (343/41570). AF 95% confidence interval is 0.00753. There are 2 homozygotes in GnomAd4. There are 356 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

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.1715T>C	p.Ile572Thr	missense	Exon 14 of 15	NP_001229886.1	P20794-2
MAK	NM_005906.6		c.1640T>C	p.Ile547Thr	missense	Exon 13 of 14	NP_005897.1	A0A140VK28
MAK	NM_001242385.2		c.1597+5140T>C		intron	N/A	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.1715T>C	p.Ile572Thr	missense	Exon 14 of 15	ENSP00000346484.3	P20794-2
MAK	ENST00000474039.5	TSL:1	c.1640T>C	p.Ile547Thr	missense	Exon 13 of 14	ENSP00000476067.1	P20794-1
MAK	ENST00000536370.6	TSL:1	c.1597+5140T>C		intron	N/A	ENSP00000442221.2	P20794-3

Frequencies

GnomAD3 genomes

AF:

0.00471

AC:

717

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00828

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00557

Gnomad ASJ

AF:

0.0138

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00312

Gnomad OTH

AF:

0.00812

GnomAD2 exomes

AF:

0.00375

AC:

943

AN:

251294

AF XY:

0.00373

show subpopulations

Gnomad AFR exome

AF:

0.00886

Gnomad AMR exome

AF:

0.00457

Gnomad ASJ exome

AF:

0.0151

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00342

Gnomad OTH exome

AF:

0.00751

GnomAD4 exome

AF:

0.00337

AC:

4921

AN:

1461834

Hom.:

Cov.:

AF XY:

0.00346

AC XY:

2519

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.00848

AC:

284

AN:

33480

American (AMR)

AF:

0.00418

AC:

187

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0146

AC:

381

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00121

AC:

104

AN:

86258

European-Finnish (FIN)

AF:

0.000150

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.0106

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00321

AC:

3564

AN:

1111976

Other (OTH)

AF:

0.00550

AC:

332

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

261

523

784

1046

1307

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

272

408

544

680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00471

AC:

717

AN:

152310

Hom.:

Cov.:

AF XY:

0.00478

AC XY:

356

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00825

AC:

343

AN:

41570

American (AMR)

AF:

0.00556

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0138

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000621

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00312

AC:

212

AN:

68014

Other (OTH)

AF:

0.00803

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

110

146

183

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00407

Hom.:

Bravo

AF:

0.00493

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.00976

AC:

ESP6500EA

AF:

0.00314

AC:

ExAC

AF:

0.00335

AC:

407

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00485

EpiControl

AF:

0.00522

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Retinitis pigmentosa 62 (2)

Retinitis Pigmentosa, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.056

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.65

M_CAP

Benign

0.023

MetaRNN

Benign

0.0096

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.55

PhyloP100

1.1

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.7

REVEL

Benign

0.13

Sift

Benign

0.040

Sift4G

Uncertain

0.059

Polyphen

0.011

Vest4

0.19

MVP

0.68

MPC

0.21

ClinPred

0.0037

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.051

gMVP

0.52

Mutation Taster

=99/1

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over