8-20197446-G-C

Variant names:

• chr8-20197446-G-C
• rs149880251
• NM_001693.4:c.40G>C

Variant summary

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

The NM_001693.4(ATP6V1B2):​c.40G>C​(p.Ala14Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000144 in 1,390,154 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A14S) has been classified as Benign.

• 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: 4.24
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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>C	p.Ala14Pro	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.40G>C	p.Ala14Pro	missense	Exon 1 of 14	ENSP00000276390.2	P21281
	ATP6V1B2	ENST00000519667.1	TSL:1	c.7G>C	p.Ala3Pro	missense	Exon 1 of 6	ENSP00000430682.1	H0YC04
	ATP6V1B2	ENST00000891263.1		c.40G>C	p.Ala14Pro	missense	Exon 1 of 15	ENSP00000561322.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1390154 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 690372

African (AFR) AF: 0.00 AC: 0 AN: 28892

American (AMR) AF: 0.00 AC: 0 AN: 35962

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23780

East Asian (EAS) AF: 0.00 AC: 0 AN: 32634

South Asian (SAS) AF: 0.00 AC: 0 AN: 79756

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4998

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1077044

Other (OTH) AF: 0.00 AC: 0 AN: 56808

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Benign	0.080
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N
PhyloP100		4.2
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	0.0	N
REVEL	Uncertain	0.37
Sift	Benign	0.11	T
Sift4G	Benign	0.34	T
Polyphen		0.96	D
Vest4		0.46
MutPred		0.29		Gain of disorder (P = 0.0294)
MVP		0.68
MPC		0.015
ClinPred		0.73	D
GERP RS		4.8
PromoterAI		-0.060	Neutral
Varity_R		0.27
gMVP		0.60
Mutation Taster		=64/36	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: rs149880251; hg19: chr8-20054957;