8-20197420-C-G

Variant names:

• chr8-20197420-C-G
• rs368067224
• NM_001693.4:c.14C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001693.4(ATP6V1B2):​c.14C>G​(p.Ala5Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,391,002 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. 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. A5E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATP6V1B2 NM_001693.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.42
• Publications: 1 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30535752).

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.14C>G	p.Ala5Gly	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.14C>G	p.Ala5Gly	missense	Exon 1 of 14	ENSP00000276390.2	P21281
	ATP6V1B2	ENST00000891263.1		c.14C>G	p.Ala5Gly	missense	Exon 1 of 15	ENSP00000561322.1
	ATP6V1B2	ENST00000958718.1		c.14C>G	p.Ala5Gly	missense	Exon 1 of 14	ENSP00000628777.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000119 AC: 2 AN: 168542 AF XY: 0.0000214

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1391002 Hom.: 0 Cov.: 31 AF XY: 0.00000289 AC XY: 2 AN XY: 690864

African (AFR) AF: 0.00 AC: 0 AN: 28820

American (AMR) AF: 0.00 AC: 0 AN: 36038

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23990

East Asian (EAS) AF: 0.0000309 AC: 1 AN: 32356

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 80054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4476

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078178

Other (OTH) AF: 0.00 AC: 0 AN: 56796

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000830 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.055
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.55	N
PhyloP100		3.4
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.27
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.028	D
Polyphen		0.0	B
Vest4		0.48
MutPred		0.32		Loss of stability (P = 0.0152)
MVP		0.36
MPC		0.015
ClinPred		0.54	D
GERP RS		3.9
PromoterAI		-0.17	Neutral
Varity_R		0.18
gMVP		0.62
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs368067224; hg19: chr8-20054931;