chr6-10770188-A-G

Position:

chr6-10770188-A-G

Variant summary

Our verdict is Benign. Variant got -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. 15/21 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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 194362.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=2}. Variant chr6-10770188-A-G is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAK	NM_001242957.3 linkuse as main transcript	c.1715T>C	p.Ile572Thr	missense_variant	14/15	ENST00000354489.7	NP_001229886.1	P20794-2F8VBW7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAK	ENST00000354489.7 linkuse as main transcript	c.1715T>C	p.Ile572Thr	missense_variant	14/15	5	NM_001242957.3	ENSP00000346484.3		P20794-2
ENSG00000272162	ENST00000480294.1 linkuse as main transcript	n.100+20490A>G		intron_variant		2		ENSP00000417929.1		F8WBI7

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

GnomAD3 exomes

AF:

0.00375

AC:

943

AN:

251294

Hom.:

AF XY:

0.00373

AC XY:

507

AN XY:

135812

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 SAS exome

AF:

0.00150

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

Gnomad4 AFR exome

AF:

0.00848

Gnomad4 AMR exome

AF:

0.00418

Gnomad4 ASJ exome

AF:

0.0146

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00121

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.00321

Gnomad4 OTH exome

AF:

0.00550

GnomAD4 genome

AF:

0.00471

AC:

717

AN:

152310

Hom.:

Cov.:

AF XY:

0.00478

AC XY:

356

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00825

Gnomad4 AMR

AF:

0.00556

Gnomad4 ASJ

AF:

0.0138

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00312

Gnomad4 OTH

AF:

0.00803

Alfa

AF:

0.00410

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 18, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	May 08, 2017	BS1,BP4; This alteration has an allele frequency that is greater than expected for the associated disease, and is predicted to be tolerated by multiple functional prediction tools. -

Retinitis pigmentosa 62

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Retinitis Pigmentosa, Recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.056

T;T;.

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.65

.;T;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.0096

T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.55

N;N;.

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.7

N;.;.

REVEL

Benign

0.13

Sift

Benign

0.040

D;.;.

Sift4G

Uncertain

0.059

T;T;T

Polyphen

0.011

B;B;.

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over