Genetic Variant NM_025029.5:c.162C>A (chr2-130182444-C-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_025029.5(MZT2B):c.162C>A(p.Asp54Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,559,498 control chromosomes in the GnomAD database, including 27 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 Benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.0056 ( 7 hom., cov: 33)

Exomes 𝑓: 0.0023 ( 20 hom. )

Consequence

MZT2B
NM_025029.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.109

Publications

1 publications found

Variant links:

Genes affected

MZT2B (HGNC:25886): (mitotic spindle organizing protein 2B) Located in cytosol; microtubule cytoskeleton; and nucleoplasm. Part of gamma-tubulin large complex. [provided by Alliance of Genome Resources, Apr 2022]

MZT2B links:

SMPD4 (HGNC:32949): (sphingomyelin phosphodiesterase 4) The protein encoded by this gene is a sphingomyelinase that catalyzes the hydrolysis of membrane sphingomyelin to form phosphorylcholine and ceramide. This gene is activated by DNA damage, cellular stress, and tumor necrosis factor, but it is downregulated by wild-type p53. The encoded protein localizes to the endoplasmic reticulum and Golgi network. [provided by RefSeq, Mar 2017]

SMPD4 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)

SMPD4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0068504214).

BP6

Variant 2-130182444-C-A is Benign according to our data. Variant chr2-130182444-C-A is described in ClinVar as Benign. ClinVar VariationId is 3387987.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00228 (3205/1407252) while in subpopulation MID AF = 0.0281 (122/4340). AF 95% confidence interval is 0.0241. There are 20 homozygotes in GnomAdExome4. There are 1690 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025029.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MZT2B	NM_025029.5	MANE Select	c.162C>A	p.Asp54Glu	missense	Exon 1 of 3	NP_079305.2
MZT2B	NM_001330282.2		c.162C>A	p.Asp54Glu	missense	Exon 1 of 4	NP_001317211.1	B8ZZ87
MZT2B	NM_001330284.2		c.162C>A	p.Asp54Glu	missense	Exon 1 of 2	NP_001317213.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MZT2B	ENST00000281871.11	TSL:1 MANE Select	c.162C>A	p.Asp54Glu	missense	Exon 1 of 3	ENSP00000281871.7	Q6NZ67
SMPD4	ENST00000409031.5	TSL:1	c.-843G>T		5_prime_UTR	Exon 1 of 20	ENSP00000386531.1	Q9NXE4-1
MZT2B	ENST00000409255.1	TSL:5	c.162C>A	p.Asp54Glu	missense	Exon 1 of 4	ENSP00000386419.1	B8ZZ87

Frequencies

GnomAD3 genomes

AF:

0.00555

AC:

845

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0120

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00510

Gnomad ASJ

AF:

0.0147

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.000754

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.00234

Gnomad OTH

AF:

0.00813

GnomAD2 exomes

AF:

0.00364

AC:

580

AN:

159534

AF XY:

0.00372

show subpopulations

Gnomad AFR exome

AF:

0.0123

Gnomad AMR exome

AF:

0.00376

Gnomad ASJ exome

AF:

0.0128

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000545

Gnomad NFE exome

AF:

0.00249

Gnomad OTH exome

AF:

0.00571

GnomAD4 exome

AF:

0.00228

AC:

3205

AN:

1407252

Hom.:

Cov.:

AF XY:

0.00243

AC XY:

1690

AN XY:

695358

show subpopulations

African (AFR)

AF:

0.0120

AC:

387

AN:

32146

American (AMR)

AF:

0.00390

AC:

145

AN:

37160

Ashkenazi Jewish (ASJ)

AF:

0.0131

AC:

330

AN:

25124

East Asian (EAS)

AF:

0.00

AC:

AN:

36844

South Asian (SAS)

AF:

0.00317

AC:

254

AN:

80104

European-Finnish (FIN)

AF:

0.000318

AC:

AN:

47096

Middle Eastern (MID)

AF:

0.0281

AC:

122

AN:

4340

European-Non Finnish (NFE)

AF:

0.00153

AC:

1666

AN:

1086204

Other (OTH)

AF:

0.00491

AC:

286

AN:

58234

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

199

398

596

795

994

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<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:

0.00556

AC:

846

AN:

152246

Hom.:

Cov.:

AF XY:

0.00559

AC XY:

416

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0120

AC:

497

AN:

41562

American (AMR)

AF:

0.00510

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0147

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00436

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000754

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00234

AC:

159

AN:

68002

Other (OTH)

AF:

0.00805

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

134

178

223

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:

0.00390

Hom.:

Bravo

AF:

0.00592

ESP6500AA

AF:

0.00786

AC:

ESP6500EA

AF:

0.00290

AC:

ExAC

AF:

0.00228

AC:

260

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0064

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.65

MetaRNN

Benign

0.0069

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

PhyloP100

0.11

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.14

REVEL

Benign

0.069

Sift

Benign

0.47

Sift4G

Benign

1.0

Polyphen

0.026

Vest4

0.057

MutPred

0.26

Gain of methylation at K57 (P = 0.1149)

MVP

0.043

MPC

1.8

ClinPred

0.0079

GERP RS

1.9

PromoterAI

-0.066

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.082

gMVP

0.10

Mutation Taster

=92/8

polymorphism

(source)

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

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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