2-70943401-C-CAG

Position:

• chr2-70943401-C-CAG

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001692.4(ATP6V1B1):​c.119-257_119-256insAG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.028 in 625,966 control chromosomes in the GnomAD database, including 308 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.024 (45 hom., cov: 32)
  • Exomes 𝑓: 0.029 (263 hom.)
• Consequence: ATP6V1B1 NM_001692.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.623

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 -10 ACMG points.

• BP6: Variant 2-70943401-C-CAG is Benign according to our data. Variant chr2-70943401-C-CAG is described in ClinVar as [Likely_benign]. Clinvar id is 1211479.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.024 (3650/152226) while in subpopulation NFE AF= 0.0355 (2412/67978). AF 95% confidence interval is 0.0343. There are 45 homozygotes in gnomad4. There are 1766 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 45 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V1B1	NM_001692.4	c.119-257_119-256insAG		intron_variant		ENST00000234396.10	NP_001683.2
ATP6V1B1-AS1	NR_110274.1	n.386-969_386-968insCT		intron_variant, non_coding_transcript_variant
ATP6V1B1-AS1	NR_110273.1	n.524-969_524-968insCT		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6V1B1	ENST00000234396.10	c.119-257_119-256insAG		intron_variant		1	NM_001692.4	ENSP00000234396	P1
ATP6V1B1-AS1	ENST00000422761.1	n.523-969_523-968insCT		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0240 AC: 3651 AN: 152108 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.00623

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0231

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0230

Gnomad FIN AF: 0.0396

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0355

Gnomad OTH AF: 0.0110

GnomAD4 exome AF: 0.0293 AC: 13873 AN: 473740 Hom.: 263 Cov.: 0 AF XY: 0.0293 AC XY: 7371 AN XY: 251960

Gnomad4 AFR exome AF: 0.00558

Gnomad4 AMR exome AF: 0.0302

Gnomad4 ASJ exome AF: 0.0101

Gnomad4 EAS exome AF: 0.000856

Gnomad4 SAS exome AF: 0.0318

Gnomad4 FIN exome AF: 0.0424

Gnomad4 NFE exome AF: 0.0331

Gnomad4 OTH exome AF: 0.0268

GnomAD4 genome AF: 0.0240 AC: 3650 AN: 152226 Hom.: 45 Cov.: 32 AF XY: 0.0237 AC XY: 1766 AN XY: 74434

Gnomad4 AFR AF: 0.00621

Gnomad4 AMR AF: 0.0231

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0228

Gnomad4 FIN AF: 0.0396

Gnomad4 NFE AF: 0.0355

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0427 Hom.: 5

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs782603378; hg19: chr2-71170531;