chr2-46512452-C-A

Variant names:

• chr2-46512452-C-A
• rs139268603
• NM_001318063.2:c.260G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001318063.2(ATP6V1E2):​c.260G>T​(p.Arg87Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R87Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ATP6V1E2 NM_001318063.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.56
• Publications: 0 publications found

Genes affected

ATP6V1E2 (HGNC:18125): (ATPase H+ transporting V1 subunit E2) Predicted to enable P-type proton-exporting transporter activity. Predicted to act upstream of or within proton transmembrane transport. Predicted to be located in cytosol. Predicted to be part of proton-transporting two-sector ATPase complex, catalytic domain. [provided by Alliance of Genome Resources, Apr 2022]

LINC02583 (HGNC:53812): (long intergenic non-protein coding RNA 2583)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318063.2. 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
	ATP6V1E2	NM_001318063.2	MANE Select	c.260G>T	p.Arg87Leu	missense	Exon 5 of 5	NP_001304992.1	A0A140VKA8
	ATP6V1E2	NM_001371281.1		c.260G>T	p.Arg87Leu	missense	Exon 5 of 5	NP_001358210.1	Q96A05
	ATP6V1E2	NM_001371282.1		c.260G>T	p.Arg87Leu	missense	Exon 5 of 5	NP_001358211.1	A0A140VKA8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V1E2	ENST00000522587.6	TSL:3 MANE Select	c.260G>T	p.Arg87Leu	missense	Exon 5 of 5	ENSP00000428141.1	Q96A05
	ATP6V1E2	ENST00000306448.4	TSL:1	c.260G>T	p.Arg87Leu	missense	Exon 2 of 2	ENSP00000304891.4	Q96A05
	ATP6V1E2	ENST00000890126.1		c.260G>T	p.Arg87Leu	missense	Exon 6 of 6	ENSP00000560185.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Benign	0.091
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Pathogenic	4.0	H
PhyloP100		2.6
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.74		Loss of MoRF binding (P = 0.0452)
MVP		0.21
MPC		0.11
ClinPred		1.0	D
GERP RS		0.52
Varity_R		0.90
gMVP		0.71
Mutation Taster		=23/77	disease causing

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: rs139268603; hg19: chr2-46739591;