11-117820671-G-A

Position:

• chr11-117820671-G-A

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.*1C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 1,613,726 control chromosomes in the GnomAD database, including 15,993 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1373 hom., cov: 32)
  • Exomes 𝑓: 0.14 (14620 hom.)
• Consequence: FXYD2 NM_001680.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.527

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 11-117820671-G-A is Benign according to our data. Variant chr11-117820671-G-A is described in ClinVar as [Benign]. Clinvar id is 302521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FXYD2	NM_001680.5	c.*1C>T		3_prime_UTR_variant	5/6	ENST00000292079.7
FXYD6-FXYD2	NM_001243598.4	c.*35C>T		3_prime_UTR_variant	9/10
FXYD6-FXYD2	NM_001204268.3	c.*1C>T		3_prime_UTR_variant	10/11
FXYD2	NM_021603.4	c.*1C>T		3_prime_UTR_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FXYD2	ENST00000292079.7	c.*1C>T		3_prime_UTR_variant	5/6	1	NM_001680.5
	ENST00000531850.2	n.487G>A		non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19627 AN: 152052 Hom.: 1370 Cov.: 32

Gnomad AFR AF: 0.0927

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.178

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.0449

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.143

GnomAD3 exomes AF: 0.139 AC: 34821 AN: 250982 Hom.: 2878 AF XY: 0.131 AC XY: 17774 AN XY: 135690

Gnomad AFR exome AF: 0.0888

Gnomad AMR exome AF: 0.233

Gnomad ASJ exome AF: 0.116

Gnomad EAS exome AF: 0.190

Gnomad SAS exome AF: 0.0403

Gnomad FIN exome AF: 0.133

Gnomad NFE exome AF: 0.139

Gnomad OTH exome AF: 0.143

GnomAD4 exome AF: 0.137 AC: 200385 AN: 1461556 Hom.: 14620 Cov.: 33 AF XY: 0.134 AC XY: 97090 AN XY: 727110

Gnomad4 AFR exome AF: 0.0930

Gnomad4 AMR exome AF: 0.225

Gnomad4 ASJ exome AF: 0.116

Gnomad4 EAS exome AF: 0.216

Gnomad4 SAS exome AF: 0.0445

Gnomad4 FIN exome AF: 0.134

Gnomad4 NFE exome AF: 0.140

Gnomad4 OTH exome AF: 0.139

GnomAD4 genome AF: 0.129 AC: 19650 AN: 152170 Hom.: 1373 Cov.: 32 AF XY: 0.129 AC XY: 9565 AN XY: 74374

Gnomad4 AFR AF: 0.0931

Gnomad4 AMR AF: 0.178

Gnomad4 ASJ AF: 0.124

Gnomad4 EAS AF: 0.191

Gnomad4 SAS AF: 0.0447

Gnomad4 FIN AF: 0.127

Gnomad4 NFE AF: 0.141

Gnomad4 OTH AF: 0.142

Alfa AF: 0.133 Hom.: 2444

Bravo AF: 0.136

Asia WGS AF: 0.110 AC: 381 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 26, 2019	- -

Renal hypomagnesemia 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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	1.9
DANN	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs869789; hg19: chr11-117691386; COSMIC: COSV52643034; COSMIC: COSV52643034;