2-130182444-C-G

Variant names:

• chr2-130182444-C-G
• NM_025029.5:c.162C>G
• MZT2B p.Asp54Glu

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_025029.5(MZT2B):​c.162C>G​(p.Asp54Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MZT2B NM_025029.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.109
• Publications: 0 publications found

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]

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: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

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

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0064	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.11
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.075
Sift	Benign	0.47	T
Sift4G	Benign	1.0	T
PromoterAI		-0.087	Neutral
Varity_R		0.082
gMVP		0.10
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.42		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.42		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr2-130940017;