Genetic Variant VPS26C:p.Thr158Lys (chr21-37232411-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_006052.2(VPS26C):c.473C>A(p.Thr158Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. 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. T158M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

VPS26C
NM_006052.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.84

Publications

0 publications found

Variant links:

Genes affected

VPS26C (HGNC:3044): (VPS26 endosomal protein sorting factor C) The region of chromosome 21 between genes CBR and ERG (CBR-ERG region), which spans 2.5 Mb on 21q22.2, has been defined by analysis of patients with partial trisomy 21. It contributes significantly to the pathogenesis of many characteristics of Down syndrome, including morphological features, hypotonia, and cognitive disability. The DSCR3 (Down syndrome critical region gene 3) gene is found in this region and is predictated to contain eight exons. DSCR3 is expressed in most tissues examined. [provided by RefSeq, Jul 2008]

VPS26C links:

ENSG00000242553 (HGNC:):

ENSG00000242553 links:

DSCR9 (HGNC:16301): (Down syndrome critical region 9)

DSCR9 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.39545912).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006052.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VPS26C	NM_006052.2	MANE Select	c.473C>A	p.Thr158Lys	missense	Exon 5 of 8	NP_006043.1	O14972-1
VPS26C	NM_001331022.1		c.392C>A	p.Thr131Lys	missense	Exon 4 of 7	NP_001317951.1	O14972-2
VPS26C	NM_001331021.1		c.329C>A	p.Thr110Lys	missense	Exon 4 of 7	NP_001317950.1	A8MY26

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VPS26C	ENST00000309117.11	TSL:1 MANE Select	c.473C>A	p.Thr158Lys	missense	Exon 5 of 8	ENSP00000311399.6	O14972-1
VPS26C	ENST00000399000.7	TSL:1	n.1292C>A		non_coding_transcript_exon	Exon 5 of 10
VPS26C	ENST00000488368.5	TSL:1	n.564C>A		non_coding_transcript_exon	Exon 6 of 9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111976

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

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

Benign

0.22

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Benign

0.95

Eigen

Benign

-0.11

Eigen_PC

Benign

0.073

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.0056

MetaRNN

Benign

0.40

MetaSVM

Benign

-0.87

PhyloP100

4.8

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.8

REVEL

Benign

0.13

Sift

Benign

0.55

Sift4G

Benign

0.50

Polyphen

0.012

Vest4

0.63

MutPred

0.57

Gain of methylation at T158 (P = 0.0116)

MVP

0.32

MPC

0.61

ClinPred

0.75

GERP RS

5.2

gMVP

0.56

Mutation Taster

=63/37

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over