Genetic Variant FXYD2:p.Glu65Asp (chr11-117820678-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001680.5(FXYD2):c.195G>T(p.Glu65Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E65E) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Consequence

FXYD2
NM_001680.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.50

Publications

2 publications found

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]

FXYD2 links:

FXYD6-FXYD2 (HGNC:39978): (FXYD6-FXYD2 readthrough) This locus represents naturally occurring read-through transcription between the neighboring FXYD domain-containing ion transport regulator 6 (GeneID 53826) and sodium/potassium-transporting ATPase subunit gamma (GeneID 486) genes on chromosome 11. One read-through transcript produces a fusion protein that shares sequence identity with each individual gene product, while another read-through transcript encodes a protein that has a distinct C-terminus and only shares sequence identity with the upstream locus (GeneID 53826). [provided by RefSeq, Aug 2011]

FXYD6-FXYD2 links:

ENSG00000254844 (HGNC:):

ENSG00000254844 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06264952).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001680.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FXYD2	NM_001680.5	MANE Select	c.195G>T	p.Glu65Asp	missense	Exon 5 of 6	NP_001671.2
FXYD6-FXYD2	NM_001204268.3		c.429G>T	p.Glu143Asp	missense	Exon 10 of 11	NP_001191197.1	A0A087WZ82
FXYD2	NM_021603.4		c.189G>T	p.Glu63Asp	missense	Exon 5 of 6	NP_067614.1	P54710-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FXYD2	ENST00000292079.7	TSL:1 MANE Select	c.195G>T	p.Glu65Asp	missense	Exon 5 of 6	ENSP00000292079.2	P54710-1
FXYD6-FXYD2	ENST00000614497.5	TSL:3	c.429G>T	p.Glu143Asp	missense	Exon 10 of 11	ENSP00000482442.1	A0A087WZ82
FXYD2	ENST00000260287.2	TSL:1	c.189G>T	p.Glu63Asp	missense	Exon 5 of 6	ENSP00000260287.2	P54710-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.97

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.14

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.061

LIST_S2

Benign

0.19

M_CAP

Benign

0.0092

MetaRNN

Benign

0.063

MetaSVM

Benign

-0.97

PhyloP100

-1.5

PROVEAN

Benign

-1.6

REVEL

Benign

0.074

Sift

Benign

0.11

Sift4G

Benign

0.29

Polyphen

0.0030

Vest4

0.21

MutPred

0.21

Gain of MoRF binding (P = 0.1775)

MVP

0.23

MPC

0.12

ClinPred

0.047

GERP RS

-2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.057

gMVP

0.087

Mutation Taster

=91/9

polymorphism

(source)

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over