2-70943405-C-T

Position:

• chr2-70943405-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001692.4(ATP6V1B1):​c.119-253C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 633,366 control chromosomes in the GnomAD database, including 207 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (41 hom., cov: 33)
  • Exomes 𝑓: 0.021 (166 hom.)
• Consequence: ATP6V1B1 NM_001692.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.428

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]

ATP6V1B1-AS1 (HGNC:51118): (ATP6V1B1 antisense RNA 1)

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-70943405-C-T is Benign according to our data. Variant chr2-70943405-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1211998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0185 (2806/151864) while in subpopulation NFE AF= 0.0282 (1913/67770). AF 95% confidence interval is 0.0272. There are 41 homozygotes in gnomad4. There are 1371 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V1B1	NM_001692.4	c.119-253C>T		intron_variant		ENST00000234396.10	NP_001683.2
ATP6V1B1-AS1	NR_110274.1	n.386-972G>A		intron_variant, non_coding_transcript_variant
ATP6V1B1-AS1	NR_110273.1	n.524-972G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6V1B1	ENST00000234396.10	c.119-253C>T		intron_variant		1	NM_001692.4	ENSP00000234396	P1
ATP6V1B1-AS1	ENST00000422761.1	n.523-972G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0185 AC: 2808 AN: 151746 Hom.: 41 Cov.: 33

Gnomad AFR AF: 0.00481

Gnomad AMI AF: 0.0606

Gnomad AMR AF: 0.0198

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0176

Gnomad FIN AF: 0.0179

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0282

Gnomad OTH AF: 0.0134

GnomAD4 exome AF: 0.0207 AC: 9964 AN: 481502 Hom.: 166 Cov.: 0 AF XY: 0.0208 AC XY: 5346 AN XY: 256464

Gnomad4 AFR exome AF: 0.00478

Gnomad4 AMR exome AF: 0.00906

Gnomad4 ASJ exome AF: 0.0110

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0203

Gnomad4 FIN exome AF: 0.0163

Gnomad4 NFE exome AF: 0.0262

Gnomad4 OTH exome AF: 0.0207

GnomAD4 genome AF: 0.0185 AC: 2806 AN: 151864 Hom.: 41 Cov.: 33 AF XY: 0.0185 AC XY: 1371 AN XY: 74256

Gnomad4 AFR AF: 0.00479

Gnomad4 AMR AF: 0.0198

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0176

Gnomad4 FIN AF: 0.0179

Gnomad4 NFE AF: 0.0282

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.0147 Hom.: 4

Bravo AF: 0.0166

Asia WGS AF: 0.00953 AC: 33 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	11
DANN	Benign	0.86

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

LitVar

Other links and lift over

dbSNP: rs115289911; hg19: chr2-71170535;