chr8-20197455-C-G

Variant names:

• chr8-20197455-C-G
• rs757469155
• NM_001693.4:c.49C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001693.4(ATP6V1B2):​c.49C>G​(p.Leu17Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000721 in 1,387,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ATP6V1B2 NM_001693.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.680
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17237979).

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.49C>G	p.Leu17Val	missense	Exon 1 of 14	NP_001684.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V1B2	ENST00000276390.7	TSL:1 MANE Select	c.49C>G	p.Leu17Val	missense	Exon 1 of 14	ENSP00000276390.2	P21281
	ATP6V1B2	ENST00000519667.1	TSL:1	c.16C>G	p.Leu6Val	missense	Exon 1 of 6	ENSP00000430682.1	H0YC04
	ATP6V1B2	ENST00000891263.1		c.49C>G	p.Leu17Val	missense	Exon 1 of 15	ENSP00000561322.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000598 AC: 1 AN: 167142 AF XY: 0.0000108

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.21e-7 AC: 1 AN: 1387436 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 688918

African (AFR) AF: 0.00 AC: 0 AN: 28778

American (AMR) AF: 0.00 AC: 0 AN: 35334

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23476

East Asian (EAS) AF: 0.00 AC: 0 AN: 32704

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79316

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5148

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1075702

Other (OTH) AF: 0.00 AC: 0 AN: 56688

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Benign	0.91
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.68
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.24
Sift	Benign	0.097	T
Sift4G	Benign	0.71	T
Polyphen		0.0010	B
Vest4		0.42
MutPred		0.18		Gain of sheet (P = 0.0477)
MVP		0.51
MPC		0.013
ClinPred		0.14	T
GERP RS		3.9
PromoterAI		0.065	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.48
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs757469155; hg19: chr8-20054966;