8-20197446-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001693.4(ATP6V1B2):c.40G>T(p.Ala14Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0019 in 1,542,432 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 24 hom., cov: 33)

Exomes 𝑓: 0.00099 ( 25 hom. )

Consequence

ATP6V1B2
NM_001693.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.24

Publications

6 publications found

Variant links:

Genes affected

ATP6V1B2 (HGNC:854): (ATPase H+ transporting V1 subunit B2) This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A, three B, and two G subunits, as well as a C, D, E, F, and H subunit. The V1 domain contains the ATP catalytic site. The protein encoded by this gene is one of two V1 domain B subunit isoforms and is the only B isoform highly expressed in osteoclasts. [provided by RefSeq, Jul 2008]

ATP6V1B2 Gene-Disease associations (from GenCC):

autosomal dominant deafness - onychodystrophy syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
developmental and epileptic encephalopathy 93
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
neurodevelopmental disorder
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
Zimmermann-Laband syndrome 2
Inheritance: AD Classification: STRONG Submitted by: G2P
DOORS syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Zimmermann-Laband syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ATP6V1B2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003306955).

BP6

Variant 8-20197446-G-T is Benign according to our data. Variant chr8-20197446-G-T is described in ClinVar as Benign. ClinVar VariationId is 783518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0102 (1557/152280) while in subpopulation AFR AF = 0.0355 (1477/41572). AF 95% confidence interval is 0.034. There are 24 homozygotes in GnomAd4. There are 720 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001693.4. 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
	ATP6V1B2	NM_001693.4	MANE Select	c.40G>T	p.Ala14Ser	missense	Exon 1 of 14	NP_001684.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP6V1B2	ENST00000276390.7	TSL:1 MANE Select	c.40G>T	p.Ala14Ser	missense	Exon 1 of 14	ENSP00000276390.2	P21281
ATP6V1B2	ENST00000519667.1	TSL:1	c.7G>T	p.Ala3Ser	missense	Exon 1 of 6	ENSP00000430682.1	H0YC04
ATP6V1B2	ENST00000891263.1		c.40G>T	p.Ala14Ser	missense	Exon 1 of 15	ENSP00000561322.1

Frequencies

GnomAD3 genomes

AF:

0.0102

AC:

1554

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0356

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00340

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00907

GnomAD2 exomes

AF:

0.00233

AC:

391

AN:

167726

AF XY:

0.00175

show subpopulations

Gnomad AFR exome

AF:

0.0396

Gnomad AMR exome

AF:

0.00200

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000956

Gnomad OTH exome

AF:

0.00158

GnomAD4 exome

AF:

0.000986

AC:

1370

AN:

1390152

Hom.:

Cov.:

AF XY:

0.000868

AC XY:

599

AN XY:

690370

show subpopulations

African (AFR)

AF:

0.0371

AC:

1073

AN:

28892

American (AMR)

AF:

0.00236

AC:

AN:

35960

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23780

East Asian (EAS)

AF:

0.00

AC:

AN:

32634

South Asian (SAS)

AF:

0.000163

AC:

AN:

79756

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50280

Middle Eastern (MID)

AF:

0.00400

AC:

AN:

4998

European-Non Finnish (NFE)

AF:

0.0000668

AC:

AN:

1077044

Other (OTH)

AF:

0.00188

AC:

107

AN:

56808

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

151

227

302

378

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.0102

AC:

1557

AN:

152280

Hom.:

Cov.:

AF XY:

0.00967

AC XY:

720

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0355

AC:

1477

AN:

41572

American (AMR)

AF:

0.00340

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68000

Other (OTH)

AF:

0.00898

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

158

236

315

394

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0208

Hom.:

2356

Bravo

AF:

0.0116

ESP6500AA

AF:

0.0347

AC:

152

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00312

AC:

376

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

Eigen

Benign

0.080

Eigen_PC

Benign

0.18

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0033

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

4.2

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.010

REVEL

Benign

0.21

Sift

Benign

0.22

Sift4G

Benign

0.77

Polyphen

0.82

Vest4

0.41

MVP

0.57

MPC

0.014

ClinPred

0.081

GERP RS

4.8

PromoterAI

0.18

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.52

Mutation Taster

=96/4

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over