X-109624334-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_012282.4(KCNE5):c.*258C>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 0.00246 in 339,508 control chromosomes in the GnomAD database, including 10 homozygotes. There are 226 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0059 (8 hom., 185 hem., cov: 24)
  • Exomes 𝑓: 0.00072 (2 hom. 41 hem.)
• Consequence: KCNE5 NM_012282.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.37

Genes affected

KCNE5 (HGNC:6241): (potassium voltage-gated channel subfamily E regulatory subunit 5) This gene encodes a member of a family of single pass transmembrane domain proteins that function as ancillary subunits to voltage-gated potassium channels. Members of this family affect diverse processes in potassium channel regulation, including ion selectivity, voltage dependence, and anterograde recycling from the plasma membrane. Variants of this gene are associated with idiopathic ventricular fibrillation and Brugada syndrome. [provided by RefSeq, Nov 2016]

ACSL4 (HGNC:3571): (acyl-CoA synthetase long chain family member 4) The protein encoded by this gene is an isozyme of the long-chain fatty-acid-coenzyme A ligase family. Although differing in substrate specificity, subcellular localization, and tissue distribution, all isozymes of this family convert free long-chain fatty acids into fatty acyl-CoA esters, and thereby play a key role in lipid biosynthesis and fatty acid degradation. This isozyme preferentially utilizes arachidonate as substrate. The absence of this enzyme may contribute to the cognitive disability or Alport syndrome. Alternative splicing of this gene generates multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant X-109624334-G-A is Benign according to our data. Variant chrX-109624334-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1318086.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00595 (670/112670) while in subpopulation AFR AF= 0.0191 (592/31033). AF 95% confidence interval is 0.0178. There are 8 homozygotes in gnomad4. There are 185 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNE5	NM_012282.4	c.*258C>T		3_prime_UTR_variant	1/1	ENST00000372101.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNE5	ENST00000372101.3	c.*258C>T		3_prime_UTR_variant	1/1		NM_012282.4	P1
ACSL4	ENST00000439581.1	n.387-13C>T		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00592 AC: 667 AN: 112616 Hom.: 8 Cov.: 24 AF XY: 0.00518 AC XY: 180 AN XY: 34768

Gnomad AFR AF: 0.0190

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00531

Gnomad ASJ AF: 0.00113

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000113

Gnomad OTH AF: 0.00791

GnomAD4 exome AF: 0.000723 AC: 164 AN: 226838 Hom.: 2 Cov.: 0 AF XY: 0.000604 AC XY: 41 AN XY: 67830

Gnomad4 AFR exome AF: 0.0207

Gnomad4 AMR exome AF: 0.00287

Gnomad4 ASJ exome AF: 0.000853

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000547

Gnomad4 OTH exome AF: 0.00155

GnomAD4 genome AF: 0.00595 AC: 670 AN: 112670 Hom.: 8 Cov.: 24 AF XY: 0.00531 AC XY: 185 AN XY: 34832

Gnomad4 AFR AF: 0.0191

Gnomad4 AMR AF: 0.00530

Gnomad4 ASJ AF: 0.00113

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000113

Gnomad4 OTH AF: 0.00781

Alfa AF: 0.00356 Hom.: 9

Bravo AF: 0.00733

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 28, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
Cadd	Benign	14
Dann	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs41313563; hg19: chrX-108867563;