chrX-109624716-T-G

Variant names:

• chrX-109624716-T-G
• rs375008004
• NM_012282.4:c.305A>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_012282.4(KCNE5):​c.305A>C​(p.Glu102Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000158 in 1,203,630 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E102K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 25)
  • Exomes 𝑓: 0.000016 (0 hom. 4 hem.)
• Consequence: KCNE5 NM_012282.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.58
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23668426).
• BS2: High AC in GnomAdExome4 at 17 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.305A>C	p.Glu102Ala	missense	Exon 1 of 1	NP_036414.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNE5	ENST00000372101.3	TSL:6 MANE Select	c.305A>C	p.Glu102Ala	missense	Exon 1 of 1	ENSP00000361173.2
	ACSL4	ENST00000439581.1	TSL:3	n.387-395A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000177 AC: 2 AN: 112887 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.0000321

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000156 AC: 17 AN: 1090743 Hom.: 0 Cov.: 31 AF XY: 0.0000112 AC XY: 4 AN XY: 358205

African (AFR) AF: 0.00 AC: 0 AN: 26242

American (AMR) AF: 0.00 AC: 0 AN: 34346

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19197

East Asian (EAS) AF: 0.00 AC: 0 AN: 29835

South Asian (SAS) AF: 0.00 AC: 0 AN: 53218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39359

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4117

European-Non Finnish (NFE) AF: 0.0000203 AC: 17 AN: 838647

Other (OTH) AF: 0.00 AC: 0 AN: 45782

GnomAD4 genome AF: 0.0000177 AC: 2 AN: 112887 Hom.: 0 Cov.: 25 AF XY: 0.0000285 AC XY: 1 AN XY: 35149

African (AFR) AF: 0.0000321 AC: 1 AN: 31147

American (AMR) AF: 0.00 AC: 0 AN: 10837

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3511

South Asian (SAS) AF: 0.00 AC: 0 AN: 2821

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 233

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53182

Other (OTH) AF: 0.00 AC: 0 AN: 1530

Alfa AF: 0.000169 Hom.: 1

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000150 AC: 1

ExAC AF: 0.00000831 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

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
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.30	T
PhyloP100		4.6
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.26
Sift	Benign	0.030	D
Sift4G	Uncertain	0.024	D
Polyphen		0.29	B
Vest4		0.11
MVP		0.076
MPC		0.45
ClinPred		0.59	D
GERP RS		4.3
PromoterAI		-0.019	Neutral
Varity_R		0.20
gMVP		0.67
Mutation Taster		=58/42	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: rs375008004; hg19: chrX-108867945;