11-117820203-A-C

Variant names:

• chr11-117820203-A-C
• rs11999
• NM_001680.5:c.*176T>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001680.5(FXYD2):​c.*176T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 167,860 control chromosomes in the GnomAD database, including 7,538 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6588 hom., cov: 32)
  • Exomes 𝑓: 0.33 (950 hom.)
• Consequence: FXYD2 NM_001680.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.289

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 11-117820203-A-C is Benign according to our data. Variant chr11-117820203-A-C is described in ClinVar as [Benign]. Clinvar id is 302515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.354 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FXYD2	NM_001680.5	c.*176T>G		3_prime_UTR_variant	Exon 6 of 6	ENST00000292079.7	NP_001671.2
FXYD6-FXYD2	NM_001204268.3	c.*176T>G		3_prime_UTR_variant	Exon 11 of 11		NP_001191197.1
FXYD6-FXYD2	NM_001243598.4	c.*210T>G		3_prime_UTR_variant	Exon 10 of 10		NP_001230527.1
FXYD2	NM_021603.4	c.*176T>G		3_prime_UTR_variant	Exon 6 of 6		NP_067614.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FXYD2	ENST00000292079	c.*176T>G		3_prime_UTR_variant	Exon 6 of 6	1	NM_001680.5	ENSP00000292079.2
FXYD6-FXYD2	ENST00000614497.5	c.*176T>G		downstream_gene_variant		3		ENSP00000482442.1

Frequencies

GnomAD3 genomes AF: 0.276 AC: 41931 AN: 151986 Hom.: 6588 Cov.: 32

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.293

Gnomad AMR AF: 0.306

Gnomad ASJ AF: 0.333

Gnomad EAS AF: 0.0955

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.319

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.357

Gnomad OTH AF: 0.279

GnomAD4 exome AF: 0.329 AC: 5183 AN: 15756 Hom.: 950 Cov.: 0 AF XY: 0.327 AC XY: 2617 AN XY: 8014

Gnomad4 AFR exome AF: 0.148

Gnomad4 AMR exome AF: 0.380

Gnomad4 ASJ exome AF: 0.377

Gnomad4 EAS exome AF: 0.0845

Gnomad4 SAS exome AF: 0.178

Gnomad4 FIN exome AF: 0.310

Gnomad4 NFE exome AF: 0.359

Gnomad4 OTH exome AF: 0.329

GnomAD4 genome AF: 0.276 AC: 41935 AN: 152104 Hom.: 6588 Cov.: 32 AF XY: 0.267 AC XY: 19871 AN XY: 74358

Gnomad4 AFR AF: 0.149

Gnomad4 AMR AF: 0.306

Gnomad4 ASJ AF: 0.333

Gnomad4 EAS AF: 0.0951

Gnomad4 SAS AF: 0.168

Gnomad4 FIN AF: 0.319

Gnomad4 NFE AF: 0.357

Gnomad4 OTH AF: 0.276

Alfa AF: 0.343 Hom.: 13543

Bravo AF: 0.273

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Renal hypomagnesemia 2 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.9
DANN	Benign	0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11999; hg19: chr11-117690918;