rs919650074

Variant names:

• chrX-109624898-G-A
• rs919650074
• NM_012282.4:c.123C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_012282.4(KCNE5):​c.123C>T​(p.Val41Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000331 in 1,208,938 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 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 0.000044 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.000032 (0 hom. 13 hem.)
• Consequence: KCNE5 NM_012282.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0100
• Publications: 0 publications found

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]

ACSL4 Gene-Disease associations (from GenCC):

• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: ClinGen, Illumina, Orphanet
• intellectual disability, X-linked 63

  Inheritance: XL Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant X-109624898-G-A is Benign according to our data. Variant chrX-109624898-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 532132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.01 with no splicing effect.
• BS2: High AC in GnomAd4 at 5 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012282.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNE5	NM_012282.4	MANE Select	c.123C>T	p.Val41Val	synonymous	Exon 1 of 1	NP_036414.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNE5	ENST00000372101.3	TSL:6 MANE Select	c.123C>T	p.Val41Val	synonymous	Exon 1 of 1	ENSP00000361173.2
	ACSL4	ENST00000439581.1	TSL:3	n.387-577C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000442 AC: 5 AN: 113076 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000940

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000284 AC: 5 AN: 176132 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000642

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000319 AC: 35 AN: 1095862 Hom.: 0 Cov.: 31 AF XY: 0.0000359 AC XY: 13 AN XY: 362342

African (AFR) AF: 0.00 AC: 0 AN: 26352

American (AMR) AF: 0.00 AC: 0 AN: 35193

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19370

East Asian (EAS) AF: 0.00 AC: 0 AN: 30198

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54056

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39636

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3166

European-Non Finnish (NFE) AF: 0.0000392 AC: 33 AN: 841919

Other (OTH) AF: 0.0000218 AC: 1 AN: 45972

GnomAD4 genome AF: 0.0000442 AC: 5 AN: 113076 Hom.: 0 Cov.: 24 AF XY: 0.0000284 AC XY: 1 AN XY: 35228

African (AFR) AF: 0.00 AC: 0 AN: 31229

American (AMR) AF: 0.00 AC: 0 AN: 10888

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3540

South Asian (SAS) AF: 0.00 AC: 0 AN: 2799

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6299

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.0000940 AC: 5 AN: 53215

Other (OTH) AF: 0.00 AC: 0 AN: 1535

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.0000302

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Brugada syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	7.2
DANN	Benign	0.90
PhyloP100		-0.010
PromoterAI		-0.070	Neutral
Mutation Taster		=100/0	polymorphism

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: rs919650074; hg19: chrX-108868127; COSMIC: COSV64508494; COSMIC: COSV64508494;