2-46512347-T-C

Variant names:

• chr2-46512347-T-C
• rs779923403
• NM_001318063.2:c.365A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001318063.2(ATP6V1E2):​c.365A>G​(p.Gln122Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ATP6V1E2 NM_001318063.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.64
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962

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.365A>G	p.Gln122Arg	missense	Exon 5 of 5	NP_001304992.1	A0A140VKA8
	ATP6V1E2	NM_001371281.1		c.365A>G	p.Gln122Arg	missense	Exon 5 of 5	NP_001358210.1	Q96A05
	ATP6V1E2	NM_001371282.1		c.365A>G	p.Gln122Arg	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.365A>G	p.Gln122Arg	missense	Exon 5 of 5	ENSP00000428141.1	Q96A05
	ATP6V1E2	ENST00000306448.4	TSL:1	c.365A>G	p.Gln122Arg	missense	Exon 2 of 2	ENSP00000304891.4	Q96A05
	ATP6V1E2	ENST00000890126.1		c.365A>G	p.Gln122Arg	missense	Exon 6 of 6	ENSP00000560185.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250852 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461720 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727148

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

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111936

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74338

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		7.6
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.036	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.89		Gain of MoRF binding (P = 0.0601)
MVP		0.36
MPC		0.11
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.96
gMVP		0.69
Mutation Taster		=45/55	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: rs779923403; hg19: chr2-46739486;