Genetic Variant NM_032357.4:c.305G>C (chr2-130341033-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_032357.4(VMA22):c.305G>C(p.Arg102Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,958 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R102Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

VMA22
NM_032357.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.50

Publications

0 publications found

Variant links:

Genes affected

VMA22 (HGNC:28178): (coiled-coil domain containing 115) The protein encoded by this gene has been observed to localize to the endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC) and coat protein complex I (COPI) vesicles in some human cells. The encoded protein shares some homology with the yeast V-ATPase assembly factor Vma22p, and the orthologous protein in mouse promotes cell proliferation and suppresses cell death. Defects in this gene are a cause of congenital disorder of glycosylation, type IIo in humans. [provided by RefSeq, Mar 2016]

VMA22 Gene-Disease associations (from GenCC):

CCDC115-CDG
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine, G2P, Orphanet

VMA22 links:

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ACMG classification

Classification was made for transcript

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_032357.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VMA22	NM_032357.4	MANE Select	c.305G>C	p.Arg102Pro	missense	Exon 4 of 5	NP_115733.2
VMA22	NM_001321118.1		c.290G>C	p.Arg97Pro	missense	Exon 4 of 5	NP_001308047.1	B8ZZ99
VMA22	NM_001321119.2		c.281G>C	p.Arg94Pro	missense	Exon 4 of 5	NP_001308048.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VMA22	ENST00000259229.7	TSL:1 MANE Select	c.305G>C	p.Arg102Pro	missense	Exon 4 of 5	ENSP00000259229.2	Q96NT0-1
VMA22	ENST00000902736.1		c.305G>C	p.Arg102Pro	missense	Exon 4 of 6	ENSP00000572795.1
VMA22	ENST00000409127.1	TSL:2	c.290G>C	p.Arg97Pro	missense	Exon 4 of 5	ENSP00000387301.1	B8ZZ99

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1452958

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722362

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33186

American (AMR)

AF:

0.00

AC:

AN:

43126

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25522

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39598

South Asian (SAS)

AF:

0.00

AC:

AN:

85040

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52804

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107998

Other (OTH)

AF:

0.00

AC:

AN:

59964

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.27

Eigen

Benign

-0.0049

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.79

M_CAP

Uncertain

0.29

MetaRNN

Uncertain

0.73

MetaSVM

Uncertain

0.49

MutationAssessor

Pathogenic

3.1

PhyloP100

1.5

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.5

REVEL

Uncertain

0.45

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.019

Polyphen

1.0

Vest4

0.55

MutPred

0.25

Loss of MoRF binding (P = 0.0185)

MVP

0.96

MPC

1.1

ClinPred

0.99

GERP RS

2.8

Varity_R

0.83

gMVP

0.76

Mutation Taster

=82/18

polymorphism

(source)

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

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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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over