17-4891112-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_153827.5(MINK1):c.1728G>C(p.Glu576Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00393 in 1,535,738 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0041 (15 hom.)
• Consequence: MINK1 NM_153827.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.292

Genes affected

MINK1 (HGNC:17565): (misshapen like kinase 1) This gene encodes a serine/threonine kinase belonging to the germinal center kinase (GCK) family. The protein is structurally similar to the kinases that are related to NIK and may belong to a distinct subfamily of NIK-related kinases within the GCK family. Studies of the mouse homolog indicate an up-regulation of expression in the course of postnatal mouse cerebral development and activation of the cJun N-terminal kinase (JNK) and the p38 pathways. [provided by RefSeq, Mar 2016]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067937076).
• BS2: High AC in GnomAd at 398 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MINK1	NM_153827.5	c.1728G>C	p.Glu576Asp	missense_variant	15/32	ENST00000355280.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MINK1	ENST00000355280.11	c.1728G>C	p.Glu576Asp	missense_variant	15/32	1	NM_153827.5	A1

Frequencies

GnomAD3 genomes AF: 0.00262 AC: 398 AN: 151838 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000984

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000625

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00450

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00223 AC: 302 AN: 135288 Hom.: 1 AF XY: 0.00198 AC XY: 144 AN XY: 72658

Gnomad AFR exome AF: 0.000541

Gnomad AMR exome AF: 0.000625

Gnomad ASJ exome AF: 0.000158

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000993

Gnomad FIN exome AF: 0.00124

Gnomad NFE exome AF: 0.00495

Gnomad OTH exome AF: 0.00267

GnomAD4 exome AF: 0.00408 AC: 5645 AN: 1383782 Hom.: 15 Cov.: 32 AF XY: 0.00388 AC XY: 2650 AN XY: 682228

Gnomad4 AFR exome AF: 0.000323

Gnomad4 AMR exome AF: 0.000799

Gnomad4 ASJ exome AF: 0.0000424

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000207

Gnomad4 FIN exome AF: 0.00191

Gnomad4 NFE exome AF: 0.00497

Gnomad4 OTH exome AF: 0.00284

GnomAD4 genome AF: 0.00262 AC: 398 AN: 151956 Hom.: 1 Cov.: 31 AF XY: 0.00232 AC XY: 172 AN XY: 74262

Gnomad4 AFR AF: 0.00150

Gnomad4 AMR AF: 0.000983

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000626

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00450

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00355 Hom.: 0

Bravo AF: 0.00240

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.00135 AC: 5

ESP6500EA AF: 0.00275 AC: 22

ExAC AF: 0.00128 AC: 134

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2023

The c.1728G>C (p.E576D) alteration is located in exon 15 (coding exon 15) of the MINK1 gene. This alteration results from a G to C substitution at nucleotide position 1728, causing the glutamic acid (E) at amino acid position 576 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.022	T;.;.
Eigen	Benign	0.039
Eigen_PC	Benign	0.056
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	D;D;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.0068	T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.4	L;L;L
MutationTaster	Benign	0.95	D;N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.49	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.29	T;T;T
Sift4G	Benign	0.58	T;T;T
Polyphen		0.92	P;P;P
Vest4		0.24
MutPred		0.094		Loss of glycosylation at P578 (P = 0.0853);Loss of glycosylation at P578 (P = 0.0853);Loss of glycosylation at P578 (P = 0.0853);
MVP		0.61
MPC		0.37
ClinPred		0.040	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.035
gMVP		0.089

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200592676; hg19: chr17-4794407;