Genetic Variant FXYD2:p.Glu65Glu (chr11-117820678-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001680.5(FXYD2):c.195G>A(p.Glu65Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00628 in 1,614,038 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0042 ( 7 hom., cov: 31)

Exomes 𝑓: 0.0065 ( 90 hom. )

Consequence

FXYD2
NM_001680.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 11-117820678-C-T is Benign according to our data. Variant chr11-117820678-C-T is described in ClinVar as Benign. ClinVar VariationId is 302522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.5 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00418 (636/152276) while in subpopulation SAS AF = 0.0195 (94/4826). AF 95% confidence interval is 0.0163. There are 7 homozygotes in GnomAd4. There are 311 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 636 AD gene.

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>A	p.Glu65Glu	synonymous	Exon 5 of 6	NP_001671.2
FXYD6-FXYD2	NM_001204268.3		c.429G>A	p.Glu143Glu	synonymous	Exon 10 of 11	NP_001191197.1	A0A087WZ82
FXYD2	NM_021603.4		c.189G>A	p.Glu63Glu	synonymous	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>A	p.Glu65Glu	synonymous	Exon 5 of 6	ENSP00000292079.2	P54710-1
FXYD6-FXYD2	ENST00000614497.5	TSL:3	c.429G>A	p.Glu143Glu	synonymous	Exon 10 of 11	ENSP00000482442.1	A0A087WZ82
FXYD2	ENST00000260287.2	TSL:1	c.189G>A	p.Glu63Glu	synonymous	Exon 5 of 6	ENSP00000260287.2	P54710-2

Frequencies

GnomAD3 genomes

AF:

0.00419

AC:

637

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00152

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0199

Gnomad FIN

AF:

0.000566

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00598

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00682

AC:

1712

AN:

251096

AF XY:

0.00779

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.0114

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00130

Gnomad NFE exome

AF:

0.00680

Gnomad OTH exome

AF:

0.00523

GnomAD4 exome

AF:

0.00650

AC:

9496

AN:

1461762

Hom.:

Cov.:

AF XY:

0.00695

AC XY:

5054

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.00122

AC:

AN:

33476

American (AMR)

AF:

0.00132

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0116

AC:

303

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0226

AC:

1946

AN:

86254

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.0114

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00595

AC:

6611

AN:

1111972

Other (OTH)

AF:

0.00652

AC:

394

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

514

1028

1541

2055

2569

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

254

508

762

1016

1270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00418

AC:

636

AN:

152276

Hom.:

Cov.:

AF XY:

0.00418

AC XY:

311

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00152

AC:

AN:

41552

American (AMR)

AF:

0.00111

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.0195

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000566

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00600

AC:

408

AN:

68008

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

130

162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00536

Hom.:

Bravo

AF:

0.00376

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.00643

EpiControl

AF:

0.00581

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Renal hypomagnesemia 2 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

1.3

(source)

DANN

Benign

0.74

PhyloP100

-1.5

Mutation Taster

=100/0

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over