Genetic Variant NM_006052.2:c.351+1022T>C (chr21-37237438-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_006052.2(VPS26C):c.351+1022T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.42 in 152,050 control chromosomes in the GnomAD database, including 13,719 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.42 ( 13717 hom., cov: 32)

Exomes 𝑓: 0.70 ( 2 hom. )

Consequence

VPS26C
NM_006052.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.140

Publications

19 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

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	Effect	Exon Rank	Protein
VPS26C	NM_006052.2	MANE Select	c.351+1022T>C	intron	N/A	NP_006043.1
VPS26C	NM_001331022.1		c.351+1022T>C	intron	N/A	NP_001317951.1
VPS26C	NM_001331021.1		c.207+1022T>C	intron	N/A	NP_001317950.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
VPS26C	ENST00000309117.11	TSL:1 MANE Select	c.351+1022T>C	intron	N/A	ENSP00000311399.6
VPS26C	ENST00000399000.7	TSL:1	n.976+1022T>C	intron	N/A
VPS26C	ENST00000488368.5	TSL:1	n.442+1022T>C	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.420

AC:

63778

AN:

151920

Hom.:

13700

Cov.:

show subpopulations

Gnomad AFR

AF:

0.376

Gnomad AMI

AF:

0.279

Gnomad AMR

AF:

0.374

Gnomad ASJ

AF:

0.378

Gnomad EAS

AF:

0.513

Gnomad SAS

AF:

0.500

Gnomad FIN

AF:

0.498

Gnomad MID

AF:

0.500

Gnomad NFE

AF:

0.435

Gnomad OTH

AF:

0.433

GnomAD4 exome

AF:

0.700

AC:

AN:

Hom.:

Cov.:

AF XY:

0.833

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.750

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.667

AC:

AN:

Other (OTH)

AC:

AN:

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

AF:

0.420

AC:

63835

AN:

152040

Hom.:

13717

Cov.:

AF XY:

0.423

AC XY:

31416

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.376

AC:

15587

AN:

41462

American (AMR)

AF:

0.374

AC:

5720

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.378

AC:

1311

AN:

3470

East Asian (EAS)

AF:

0.512

AC:

2644

AN:

5160

South Asian (SAS)

AF:

0.500

AC:

2412

AN:

4824

European-Finnish (FIN)

AF:

0.498

AC:

5265

AN:

10572

Middle Eastern (MID)

AF:

0.510

AC:

149

AN:

292

European-Non Finnish (NFE)

AF:

0.435

AC:

29564

AN:

67964

Other (OTH)

AF:

0.440

AC:

930

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1873

3746

5618

7491

9364

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

606

1212

1818

2424

3030

<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:

0.421

Hom.:

23214

Bravo

AF:

0.406

Asia WGS

AF:

0.527

AC:

1833

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

5.9

(source)

DANN

Benign

0.52

PhyloP100

0.14

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over