11-117820687-A-T

Position:

• chr11-117820687-A-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001680.5(FXYD2):​c.186T>A​(p.Asn62Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: FXYD2 NM_001680.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.203

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]

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]

ENSG00000254844 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1407333).
• BS2: High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FXYD2	NM_001680.5	c.186T>A	p.Asn62Lys	missense_variant	5/6	ENST00000292079.7	NP_001671.2
FXYD6-FXYD2	NM_001204268.3	c.420T>A	p.Asn140Lys	missense_variant	10/11		NP_001191197.1
FXYD2	NM_021603.4	c.180T>A	p.Asn60Lys	missense_variant	5/6		NP_067614.1
FXYD6-FXYD2	NM_001243598.4	c.*19T>A		3_prime_UTR_variant	9/10		NP_001230527.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FXYD2	ENST00000292079.7	c.186T>A	p.Asn62Lys	missense_variant	5/6	1	NM_001680.5	ENSP00000292079.2
FXYD6-FXYD2	ENST00000614497.5	c.420T>A	p.Asn140Lys	missense_variant	10/11	3		ENSP00000482442.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251090 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135742

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: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461770 Hom.: 0 Cov.: 33 AF XY: 0.0000151 AC XY: 11 AN XY: 727184

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: 0.0000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Renal hypomagnesemia 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.77
DANN	Benign	0.84
DEOGEN2	Benign	0.13	.;.;T;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.27	.;.;T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Benign	-0.99	T
PROVEAN	Benign	-1.3	N;N;N;N;.
REVEL	Benign	0.070
Sift	Benign	0.24	T;T;T;T;.
Sift4G	Benign	0.16	T;T;T;T;T
Polyphen		0.40	B;B;P;B;.
Vest4		0.24
MutPred		0.50		.;.;Gain of methylation at N62 (P = 0.0028);.;.;
MVP		0.73
MPC		0.25
ClinPred		0.11	T
GERP RS		-4.2
Varity_R		0.12
gMVP		0.091

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

LitVar

Other links and lift over

dbSNP: rs1044799074; hg19: chr11-117691402;