rs527738649

Variant names:

• chr2-70936031-T-C
• rs527738649
• NM_001692.4:c.77T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-70936031-T-C
• chr2-70936031-T-G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001692.4(ATP6V1B1):​c.77T>C​(p.Met26Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000289 in 1,613,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M26V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: ATP6V1B1 NM_001692.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 0.879
• Publications: 0 publications found

Genes affected

ATP6V1B1 (HGNC:853): (ATPase H+ transporting V1 subunit B1) 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 and three B subunits, two G subunits plus the C, D, E, F, and H subunits. The V1 domain contains the ATP catalytic site. The V0 domain consists of five different subunits: a, c, c', c'', and d. Additional isoforms of many of the V1 and V0 subunit proteins are encoded by multiple genes or alternatively spliced transcript variants. This encoded protein is one of two V1 domain B subunit isoforms and is found in the kidney. Mutations in this gene cause distal renal tubular acidosis associated with sensorineural deafness. [provided by RefSeq, Jul 2008]

VAX2 (HGNC:12661): (ventral anterior homeobox 2) This gene encodes a homeobox protein and is almost exclusively expressed in the ventral portion of the retina during development. In mouse studies, this gene was found to be required for the correct formation of the optic fissure and other aspects of retinal development. [provided by RefSeq, Sep 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0071368217).
• BP6: Variant 2-70936031-T-C is Benign according to our data. Variant chr2-70936031-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 227184.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001692.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V1B1	NM_001692.4	MANE Select	c.77T>C	p.Met26Thr	missense	Exon 1 of 14	NP_001683.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V1B1	ENST00000234396.10	TSL:1 MANE Select	c.77T>C	p.Met26Thr	missense	Exon 1 of 14	ENSP00000234396.4
	ATP6V1B1	ENST00000412314.5	TSL:5	c.77T>C	p.Met26Thr	missense	Exon 1 of 14	ENSP00000388353.1
	ATP6V1B1	ENST00000454446.6	TSL:5	c.77T>C	p.Met26Thr	missense	Exon 1 of 9	ENSP00000408361.2

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 151994 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000324

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000366 AC: 92 AN: 251172 AF XY: 0.000353

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00277

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000297 AC: 434 AN: 1461730 Hom.: 0 Cov.: 38 AF XY: 0.000292 AC XY: 212 AN XY: 727178

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.000425 AC: 19 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.000932 AC: 37 AN: 39694

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.000306 AC: 340 AN: 1111932

Other (OTH) AF: 0.000315 AC: 19 AN: 60382

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152112 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74370

African (AFR) AF: 0.0000241 AC: 1 AN: 41510

American (AMR) AF: 0.000196 AC: 3 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000324 AC: 22 AN: 67964

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000161 Hom.: 0

Bravo AF: 0.000257

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000296 AC: 36

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	ATP6V1B1-related disorder (1)
-	-	1	not specified (1)
-	1	-	Renal tubular acidosis with progressive nerve deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	13
DANN	Benign	0.82
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.14	N
PhyloP100		0.88
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.14
Sift	Benign	0.20	T
Sift4G	Benign	0.62	T
Polyphen		0.0	B
Vest4		0.11
MVP		0.66
MPC		0.35
ClinPred		0.0034	T
GERP RS		1.1
PromoterAI		0.071	Neutral
Varity_R		0.085
gMVP		0.34
Mutation Taster		=97/3	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: rs527738649; hg19: chr2-71163161;