Genetic Variant ENKUR:p.Arg161Gln (chr10-24990575-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_145010.4(ENKUR):c.482G>A(p.Arg161Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000236 in 1,612,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

ENKUR
NM_145010.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.99

Publications

3 publications found

Variant links:

Genes affected

ENKUR (HGNC:28388): (enkurin, TRPC channel interacting protein) This gene encodes a protein that interacts with calmodulin and several transient receptor potential canonical cation channel proteins. The encoded protein may function as an adaptor to localize signal transduction machinery to calcium channels. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2012]

ENKUR links:

ENSG00000285859 (HGNC:):

ENSG00000285859 links:

THNSL1 (HGNC:26160): (threonine synthase like 1)

THNSL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENKUR	NM_145010.4 link	c.482G>A	p.Arg161Gln	missense_variant	Exon 4 of 6	ENST00000331161.9	NP_659447.1	Q8TC29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENKUR	ENST00000331161.9 link	c.482G>A	p.Arg161Gln	missense_variant	Exon 4 of 6	1	NM_145010.4	ENSP00000331044.4		Q8TC29

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000160

AC:

AN:

249834

AF XY:

0.0000222

show subpopulations

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:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1460744

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

726664

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33362

American (AMR)

AF:

0.00

AC:

AN:

44456

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.0000233

AC:

AN:

85888

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000225

AC:

AN:

1111760

Other (OTH)

AF:

0.0000497

AC:

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41412

American (AMR)

AF:

0.0000654

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000216

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 19, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.482G>A (p.R161Q) alteration is located in exon 4 (coding exon 4) of the ENKUR gene. This alteration results from a G to A substitution at nucleotide position 482, causing the arginine (R) at amino acid position 161 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.21

T;.;T;T

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.90

.;D;D;D

M_CAP

Benign

0.016

MetaRNN

Uncertain

0.66

D;D;D;D

MetaSVM

Uncertain

-0.087

MutationAssessor

Pathogenic

3.0

M;.;.;.

PhyloP100

5.0

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.6

D;.;D;.

REVEL

Benign

0.28

Sift

Uncertain

0.0080

D;.;D;.

Sift4G

Uncertain

0.042

D;D;D;.

Polyphen

1.0

D;.;D;.

Vest4

0.81

MutPred

0.62

Loss of ubiquitination at K166 (P = 0.063);.;Loss of ubiquitination at K166 (P = 0.063);.;

MVP

0.11

MPC

0.27

ClinPred

0.95

GERP RS

5.6

Varity_R

0.58

gMVP

0.76

Mutation Taster

=43/57

disease causing

(source)

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

Publications

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10-24990575-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over