2-46512049-G-C

Variant names:

• chr2-46512049-G-C
• rs1307328073
• NM_001318063.2:c.663C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001318063.2(ATP6V1E2):​c.663C>G​(p.Asn221Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,446,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ATP6V1E2 NM_001318063.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37865967).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6V1E2	NM_001318063.2	c.663C>G	p.Asn221Lys	missense_variant	Exon 5 of 5	ENST00000522587.6	NP_001304992.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6V1E2	ENST00000522587.6	c.663C>G	p.Asn221Lys	missense_variant	Exon 5 of 5	3	NM_001318063.2	ENSP00000428141.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1446380 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 718590

African (AFR) AF: 0.00 AC: 0 AN: 32738

American (AMR) AF: 0.0000238 AC: 1 AN: 42018

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39598

South Asian (SAS) AF: 0.00 AC: 0 AN: 83380

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52870

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5680

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105364

Other (OTH) AF: 0.00 AC: 0 AN: 59692

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.663C>G (p.N221K) alteration is located in exon 2 (coding exon 1) of the ATP6V1E2 gene. This alteration results from a C to G substitution at nucleotide position 663, causing the asparagine (N) at amino acid position 221 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	.;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.38	T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.8	M;M
PhyloP100		1.6
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.92	P;P
Vest4		0.30
MutPred		0.59		Gain of methylation at N221 (P = 0.0037);Gain of methylation at N221 (P = 0.0037);
MVP		0.30
MPC		0.076
ClinPred		0.99	D
GERP RS		1.3
Varity_R		0.72
gMVP		0.65
Mutation Taster		=51/49	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

Publications

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Other links and lift over

dbSNP: rs1307328073; hg19: chr2-46739188;