rs529623

Variant names:

• chr11-117822540-T-C
• rs529623
• ENST00000317594.6:n.269A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The ENST00000317594.6(FXYD2):​n.269A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.517 in 1,555,572 control chromosomes in the GnomAD database, including 211,077 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (17756 hom., cov: 31)
  • Exomes 𝑓: 0.52 (193321 hom.)
• Consequence: FXYD2 ENST00000317594.6 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.848
• Publications: 15 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.048).
• BP6: Variant 11-117822540-T-C is Benign according to our data. Variant chr11-117822540-T-C is described in ClinVar as Benign. ClinVar VariationId is 1251788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FXYD2	NM_001680.5	c.65-60A>G		intron_variant	Intron 2 of 5	ENST00000292079.7	NP_001671.2
FXYD6-FXYD2	NM_001204268.3	c.299-60A>G		intron_variant	Intron 7 of 10		NP_001191197.1
FXYD6-FXYD2	NM_001243598.4	c.311+139A>G		intron_variant	Intron 7 of 9		NP_001230527.1
FXYD2	NM_021603.4	c.59-60A>G		intron_variant	Intron 2 of 5		NP_067614.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FXYD2	ENST00000292079.7	c.65-60A>G		intron_variant	Intron 2 of 5	1	NM_001680.5	ENSP00000292079.2
FXYD6-FXYD2	ENST00000614497.5	c.299-60A>G		intron_variant	Intron 7 of 10	3		ENSP00000482442.1

Frequencies

GnomAD3 genomes AF: 0.469 AC: 71139 AN: 151786 Hom.: 17737 Cov.: 31

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.496

Gnomad AMR AF: 0.539

Gnomad ASJ AF: 0.546

Gnomad EAS AF: 0.555

Gnomad SAS AF: 0.550

Gnomad FIN AF: 0.637

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.521

Gnomad OTH AF: 0.474

GnomAD2 exomes AF: 0.540 AC: 87550 AN: 162008 AF XY: 0.540

Gnomad AFR exome AF: 0.286

Gnomad AMR exome AF: 0.600

Gnomad ASJ exome AF: 0.560

Gnomad EAS exome AF: 0.576

Gnomad FIN exome AF: 0.632

Gnomad NFE exome AF: 0.523

Gnomad OTH exome AF: 0.542

GnomAD4 exome AF: 0.522 AC: 733219 AN: 1403666 Hom.: 193321 Cov.: 66 AF XY: 0.523 AC XY: 362279 AN XY: 692530

African (AFR) AF: 0.278 AC: 8932 AN: 32136

American (AMR) AF: 0.595 AC: 21316 AN: 35798

Ashkenazi Jewish (ASJ) AF: 0.558 AC: 14048 AN: 25198

East Asian (EAS) AF: 0.524 AC: 19090 AN: 36416

South Asian (SAS) AF: 0.544 AC: 43324 AN: 79576

European-Finnish (FIN) AF: 0.634 AC: 31396 AN: 49554

Middle Eastern (MID) AF: 0.473 AC: 2695 AN: 5702

European-Non Finnish (NFE) AF: 0.520 AC: 562296 AN: 1081126

Other (OTH) AF: 0.518 AC: 30122 AN: 58160

GnomAD4 genome AF: 0.469 AC: 71192 AN: 151906 Hom.: 17756 Cov.: 31 AF XY: 0.475 AC XY: 35284 AN XY: 74262

African (AFR) AF: 0.286 AC: 11849 AN: 41412

American (AMR) AF: 0.540 AC: 8242 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.546 AC: 1892 AN: 3468

East Asian (EAS) AF: 0.554 AC: 2850 AN: 5140

South Asian (SAS) AF: 0.551 AC: 2654 AN: 4818

European-Finnish (FIN) AF: 0.637 AC: 6729 AN: 10566

Middle Eastern (MID) AF: 0.507 AC: 149 AN: 294

European-Non Finnish (NFE) AF: 0.521 AC: 35371 AN: 67924

Other (OTH) AF: 0.478 AC: 1006 AN: 2106

Alfa AF: 0.509 Hom.: 40245

Bravo AF: 0.458

Asia WGS AF: 0.543 AC: 1887 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.1
DANN	Benign	0.27
PhyloP100		0.85
Mutation Taster		=100/0	polymorphism (auto)

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: rs529623; hg19: chr11-117693255; COSMIC: COSV52642312; COSMIC: COSV52642312;