2-130342033-CAA-ACT

Variant names:

• chr2-130342033-CAA-ACT
• NM_032357.4:c.91_93delTTGinsAGT
• VMA22 p.Leu31Ser

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS1_Very_Strong

The NM_032357.4(VMA22):​c.91_93delTTGinsAGT​(p.Leu31Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L31F) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: VMA22 NM_032357.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.69
• Publications: 0 publications found

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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS1: Transcript NM_032357.4 (VMA22) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VMA22	NM_032357.4	MANE Select	c.91_93delTTGinsAGT	p.Leu31Ser	missense	N/A	NP_115733.2
	VMA22	NM_001321118.1		c.97-91_97-89delTTGinsAGT		intron	N/A	NP_001308047.1	B8ZZ99
	VMA22	NM_001321119.2		c.87+4_87+6delTTGinsAGT		splice_region intron	N/A	NP_001308048.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VMA22	ENST00000259229.7	TSL:1 MANE Select	c.91_93delTTGinsAGT	p.Leu31Ser	missense	N/A	ENSP00000259229.2	Q96NT0-1
	VMA22	ENST00000902736.1		c.91_93delTTGinsAGT	p.Leu31Ser	missense	N/A	ENSP00000572795.1
	VMA22	ENST00000912734.1		c.91_93delTTGinsAGT	p.Leu31Ser	missense	N/A	ENSP00000582793.1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.7

Splicing

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: chr2-131099606;