Genetic Variant CLUH:p.Lys1183Arg (chr17-2692373-T-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001366661.1(CLUH):c.3548A>G(p.Lys1183Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000189 in 1,585,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

CLUH
NM_001366661.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.14

Variant links:

Genes affected

CLUH (HGNC:29094): (clustered mitochondria homolog) Enables mRNA binding activity. Involved in intracellular distribution of mitochondria. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

CLUH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21274251).

BS2

High AC in GnomAdExome4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLUH	NM_001366661.1 link	c.3548A>G	p.Lys1183Arg	missense_variant	Exon 22 of 26	ENST00000651024.2	NP_001353590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLUH	ENST00000651024.2 link	c.3548A>G	p.Lys1183Arg	missense_variant	Exon 22 of 26		NM_001366661.1	ENSP00000498679.1		A0A494C0R8

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000946

AC:

AN:

211342

Hom.:

AF XY:

0.0000257

AC XY:

AN XY:

116950

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000622

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.0000195

AC:

AN:

1433484

Hom.:

Cov.:

AF XY:

0.00000842

AC XY:

AN XY:

712398

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000583

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000271

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000680

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000752

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3431A>G (p.K1144R) alteration is located in exon 22 (coding exon 21) of the CLUH gene. This alteration results from a A to G substitution at nucleotide position 3431, causing the lysine (K) at amino acid position 1144 to be replaced by an arginine (R). 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

0.11

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

T;T;T

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.85

D;.;.

M_CAP

Pathogenic

0.29

MetaRNN

Benign

0.21

T;T;T

MetaSVM

Pathogenic

0.95

MutationAssessor

Uncertain

2.6

M;M;.

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-2.1

N;.;.

REVEL

Pathogenic

0.69

Sift

Uncertain

0.011

D;.;.

Sift4G

Uncertain

0.027

D;D;.

Polyphen

0.95

P;P;.

Vest4

0.84

MutPred

0.50

Loss of methylation at K1144 (P = 0.0144);Loss of methylation at K1144 (P = 0.0144);.;

MVP

0.79

MPC

0.87

ClinPred

0.38

GERP RS

4.9

Varity_R

0.30

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over