11-117820660-G-T

Position:

• chr11-117820660-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001680.5(FXYD2):​c.*6+6C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00965 in 1,613,678 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0099 (80 hom.)
• Consequence: FXYD2 NM_001680.5 splice_region, intron
• Scores: Splicing: ADA: 0.00009384
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.158

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 11-117820660-G-T is Benign according to our data. Variant chr11-117820660-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 302520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117820660-G-T is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 1118 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FXYD2	NM_001680.5	c.*6+6C>A		splice_region_variant, intron_variant		ENST00000292079.7	NP_001671.2
FXYD6-FXYD2	NM_001204268.3	c.*6+6C>A		splice_region_variant, intron_variant			NP_001191197.1
FXYD6-FXYD2	NM_001243598.4	c.*40+6C>A		splice_region_variant, intron_variant			NP_001230527.1
FXYD2	NM_021603.4	c.*6+6C>A		splice_region_variant, intron_variant			NP_067614.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FXYD2	ENST00000292079.7	c.*6+6C>A		splice_region_variant, intron_variant		1	NM_001680.5	ENSP00000292079.2
FXYD6-FXYD2	ENST00000614497.5	c.*6+6C>A		splice_region_variant, intron_variant		3		ENSP00000482442.1

Frequencies

GnomAD3 genomes AF: 0.00736 AC: 1119 AN: 152062 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00669 AC: 1678 AN: 250894 Hom.: 14 AF XY: 0.00686 AC XY: 930 AN XY: 135658

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00437

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00307

Gnomad FIN exome AF: 0.0110

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.00621

GnomAD4 exome AF: 0.00989 AC: 14449 AN: 1461498 Hom.: 80 Cov.: 31 AF XY: 0.00977 AC XY: 7102 AN XY: 727070

Gnomad4 AFR exome AF: 0.00128

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00444

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00318

Gnomad4 FIN exome AF: 0.0109

Gnomad4 NFE exome AF: 0.0116

Gnomad4 OTH exome AF: 0.00749

GnomAD4 genome AF: 0.00735 AC: 1118 AN: 152180 Hom.: 5 Cov.: 32 AF XY: 0.00707 AC XY: 526 AN XY: 74408

Gnomad4 AFR AF: 0.00152

Gnomad4 AMR AF: 0.00347

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0107

Gnomad4 NFE AF: 0.0116

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00733 Hom.: 2

Bravo AF: 0.00634

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

-

- -

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	-0.83
CADD	Benign	0.59
DANN	Benign	0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000094
dbscSNV1_RF	Benign	0.0
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: rs11827585; hg19: chr11-117691375;