rs387906648

Positions:

• chr6-10803886-C-G
• chr6-10803886-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_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. 12/21 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 Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAK NM_001242957.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.70

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]

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]

ENSG00000272162 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-10803887-G-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAK	NM_001242957.3	c.497G>C	p.Arg166Pro	missense_variant	7/15	ENST00000354489.7	NP_001229886.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAK	ENST00000354489.7	c.497G>C	p.Arg166Pro	missense_variant	7/15	5	NM_001242957.3	ENSP00000346484.3
ENSG00000272162	ENST00000480294.1	n.100+54188C>G		intron_variant		2		ENSP00000417929.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Pathogenic	3.7	H;H;H;H;.
PrimateAI	Pathogenic	0.89	D
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	D
GERP RS		5.4
Varity_R		0.99
gMVP		0.96

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

LitVar

Other links and lift over

dbSNP: rs387906648; hg19: chr6-10804119;