11-117820686-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001680.5(FXYD2):​c.187G>A​(p.Glu63Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

FXYD2
NM_001680.5 missense

Scores

2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.74
Variant links:
Genes affected
FXYD2 (HGNC:4026): (FXYD domain containing ion transport regulator 2) This gene encodes a member of the FXYD family of transmembrane proteins. This particular protein encodes the sodium/potassium-transporting ATPase subunit gamma. Mutations in this gene have been associated with Renal Hypomagnesemia-2. Alternatively spliced transcript variants have been described. Read-through transcripts have been observed between this locus and the upstream FXYD domain-containing ion transport regulator 6 (FXYD6, GeneID 53826) locus.[provided by RefSeq, Feb 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.32977116).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FXYD2NM_001680.5 linkuse as main transcriptc.187G>A p.Glu63Lys missense_variant 5/6 ENST00000292079.7
FXYD6-FXYD2NM_001243598.4 linkuse as main transcriptc.*20G>A 3_prime_UTR_variant 9/10
FXYD6-FXYD2NM_001204268.3 linkuse as main transcriptc.421G>A p.Glu141Lys missense_variant 10/11
FXYD2NM_021603.4 linkuse as main transcriptc.181G>A p.Glu61Lys missense_variant 5/6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FXYD2ENST00000292079.7 linkuse as main transcriptc.187G>A p.Glu63Lys missense_variant 5/61 NM_001680.5 P54710-1
ENST00000531850.2 linkuse as main transcriptn.502C>T non_coding_transcript_exon_variant 2/35

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152136
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000797
AC:
2
AN:
251076
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135740
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461782
Hom.:
0
Cov.:
33
AF XY:
0.00000275
AC XY:
2
AN XY:
727194
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152136
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74314
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000312
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 26, 2023In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with FXYD2-related conditions. This variant is present in population databases (rs760465825, gnomAD 0.002%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 63 of the FXYD2 protein (p.Glu63Lys). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.087
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.15
.;.;T;.;.
Eigen
Benign
-0.36
Eigen_PC
Benign
-0.47
FATHMM_MKL
Benign
0.26
N
LIST_S2
Benign
0.53
.;.;T;T;T
M_CAP
Benign
0.084
D
MetaRNN
Benign
0.33
T;T;T;T;T
MetaSVM
Benign
-0.76
T
MutationTaster
Benign
0.73
N;N;N;N;N;N
PROVEAN
Benign
-1.4
N;N;N;N;.
REVEL
Benign
0.082
Sift
Benign
0.070
T;T;T;T;.
Sift4G
Uncertain
0.026
D;D;D;D;D
Polyphen
0.72
P;P;P;P;.
Vest4
0.47
MutPred
0.46
.;.;Gain of MoRF binding (P = 0.0025);.;.;
MVP
0.49
MPC
0.24
ClinPred
0.17
T
GERP RS
3.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.11
gMVP
0.24

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs760465825; hg19: chr11-117691401; API