X-109624672-C-T

Variant names:

• chrX-109624672-C-T
• rs951525284
• NM_012282.4:c.349G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_012282.4(KCNE5):​c.349G>A​(p.Ala117Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000946 in 1,056,689 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A117A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000095 (0 hom. 1 hem.)
• Consequence: KCNE5 NM_012282.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.485
• Publications: 1 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: Illumina, ClinGen, Orphanet
• intellectual disability, X-linked 63

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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.051585793).
• BS2: High AC in GnomAdExome4 at 10 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNE5	NM_012282.4	MANE Select	c.349G>A	p.Ala117Thr	missense	Exon 1 of 1	NP_036414.1	Q9UJ90

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNE5	ENST00000372101.3	TSL:6 MANE Select	c.349G>A	p.Ala117Thr	missense	Exon 1 of 1	ENSP00000361173.2	Q9UJ90
	ACSL4	ENST00000439581.1	TSL:3	n.387-351G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD2 exomes AF: 0.00 AC: 0 AN: 106715 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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000946 AC: 10 AN: 1056689 Hom.: 0 Cov.: 31 AF XY: 0.00000292 AC XY: 1 AN XY: 342737

African (AFR) AF: 0.00 AC: 0 AN: 25159

American (AMR) AF: 0.00 AC: 0 AN: 28551

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18465

East Asian (EAS) AF: 0.00 AC: 0 AN: 27579

South Asian (SAS) AF: 0.00 AC: 0 AN: 50017

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36166

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3902

European-Non Finnish (NFE) AF: 0.0000122 AC: 10 AN: 822361

Other (OTH) AF: 0.00 AC: 0 AN: 44489

GnomAD4 genome Cov.: 25

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Brugada syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	6.7
DANN	Benign	0.94
DEOGEN2	Benign	0.081	T
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.48
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.053
Sift	Benign	0.044	D
Sift4G	Benign	0.32	T
Polyphen		0.012	B
Vest4		0.082
MutPred		0.14		Gain of glycosylation at A117 (P = 0.0362)
MVP		0.048
MPC		0.46
ClinPred		0.039	T
GERP RS		-2.1
PromoterAI		-0.026	Neutral
Varity_R		0.045
gMVP		0.12
Mutation Taster		=98/2	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: rs951525284; hg19: chrX-108867901;