rs28938168

Variant names:

• chr11-117822424-C-A
• rs28938168
• NM_001680.5:c.121G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-117822424-C-A
• chr11-117822424-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_001680.5(FXYD2):​c.121G>T​(p.Gly41Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,408,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G41R) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: FXYD2 NM_001680.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.23
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-117822424-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 7684.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FXYD2	NM_001680.5	MANE Select	c.121G>T	p.Gly41Trp	missense	Exon 3 of 6	NP_001671.2
	FXYD6-FXYD2	NM_001204268.3		c.355G>T	p.Gly119Trp	missense	Exon 8 of 11	NP_001191197.1
	FXYD2	NM_021603.4		c.115G>T	p.Gly39Trp	missense	Exon 3 of 6	NP_067614.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FXYD2	ENST00000292079.7	TSL:1 MANE Select	c.121G>T	p.Gly41Trp	missense	Exon 3 of 6	ENSP00000292079.2
	FXYD6-FXYD2	ENST00000614497.5	TSL:3	c.355G>T	p.Gly119Trp	missense	Exon 8 of 11	ENSP00000482442.1
	FXYD2	ENST00000260287.2	TSL:1	c.115G>T	p.Gly39Trp	missense	Exon 3 of 6	ENSP00000260287.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1408088 Hom.: 0 Cov.: 35 AF XY: 0.00000144 AC XY: 1 AN XY: 695186

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32378

American (AMR) AF: 0.00 AC: 0 AN: 36430

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25244

East Asian (EAS) AF: 0.0000270 AC: 1 AN: 36978

South Asian (SAS) AF: 0.00 AC: 0 AN: 79792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49838

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1083358

Other (OTH) AF: 0.00 AC: 0 AN: 58386

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.73	D
PhyloP100		3.2
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.82		Gain of MoRF binding (P = 0.043)
MVP		0.69
MPC		0.67
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.67
Mutation Taster		=8/92	disease causing

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

Other links and lift over

dbSNP: rs28938168; hg19: chr11-117693139;