chr2-70943683-C-T

Variant names:

• chr2-70943683-C-T
• rs144845223
• NM_001692.4:c.144C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001692.4(ATP6V1B1):​c.144C>T​(p.Asn48Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,613,866 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (21 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (10 hom.)
• Consequence: ATP6V1B1 NM_001692.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.505
• 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]

ENSG00000258881 (HGNC:):

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]

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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 2-70943683-C-T is Benign according to our data. Variant chr2-70943683-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 162759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.505 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00728 (1108/152228) while in subpopulation AFR AF = 0.0249 (1033/41528). AF 95% confidence interval is 0.0236. There are 21 homozygotes in GnomAd4. There are 496 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V1B1	NM_001692.4	MANE Select	c.144C>T	p.Asn48Asn	synonymous	Exon 2 of 14	NP_001683.2
	ATP6V1B1-AS1	NR_110273.1		n.524-1250G>A		intron	N/A
	ATP6V1B1-AS1	NR_110274.1		n.386-1250G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V1B1	ENST00000234396.10	TSL:1 MANE Select	c.144C>T	p.Asn48Asn	synonymous	Exon 2 of 14	ENSP00000234396.4	P15313
	ENSG00000258881	ENST00000606025.5	TSL:5	c.476-1250G>A		intron	N/A	ENSP00000475641.1	U3KQ87
	ATP6V1B1	ENST00000872157.1		c.144C>T	p.Asn48Asn	synonymous	Exon 2 of 14	ENSP00000542216.1

Frequencies

GnomAD3 genomes AF: 0.00728 AC: 1107 AN: 152110 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00198 AC: 496 AN: 250858 AF XY: 0.00149

Gnomad AFR exome AF: 0.0273

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000718 AC: 1049 AN: 1461638 Hom.: 10 Cov.: 33 AF XY: 0.000608 AC XY: 442 AN XY: 727124

African (AFR) AF: 0.0242 AC: 809 AN: 33480

American (AMR) AF: 0.00130 AC: 58 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53230

Middle Eastern (MID) AF: 0.000868 AC: 5 AN: 5760

European-Non Finnish (NFE) AF: 0.0000782 AC: 87 AN: 1111982

Other (OTH) AF: 0.00144 AC: 87 AN: 60382

GnomAD4 genome AF: 0.00728 AC: 1108 AN: 152228 Hom.: 21 Cov.: 32 AF XY: 0.00666 AC XY: 496 AN XY: 74422

African (AFR) AF: 0.0249 AC: 1033 AN: 41528

American (AMR) AF: 0.00392 AC: 60 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67982

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00372 Hom.: 5

Bravo AF: 0.00820

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Renal tubular acidosis with progressive nerve deafness (2)
-	-	1	ATP6V1B1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	6.6
DANN	Benign	0.80
PhyloP100		-0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	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: rs144845223; hg19: chr2-71170813;