chr17-2691889-C-T

Position:

• chr17-2691889-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001366661.1(CLUH):​c.3661G>A​(p.Glu1221Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,384,520 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: CLUH NM_001366661.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.782

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLUH	NM_001366661.1	c.3661G>A	p.Glu1221Lys	missense_variant	24/26	ENST00000651024.2	NP_001353590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLUH	ENST00000651024.2	c.3661G>A	p.Glu1221Lys	missense_variant	24/26		NM_001366661.1	ENSP00000498679.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.22e-7 AC: 1 AN: 1384520 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 683284

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.30e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 26, 2024

The c.3544G>A (p.E1182K) alteration is located in exon 24 (coding exon 23) of the CLUH gene. This alteration results from a G to A substitution at nucleotide position 3544, causing the glutamic acid (E) at amino acid position 1182 to be replaced by a lysine (K). 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	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;T;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;.;.
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Uncertain	0.0098	D
MutationAssessor	Uncertain	2.2	M;M;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.1	D;.;.
REVEL	Pathogenic	0.69
Sift	Benign	0.060	T;.;.
Sift4G	Benign	0.069	T;T;.
Polyphen		0.96	D;D;.
Vest4		0.84
MutPred		0.54		Gain of methylation at E1182 (P = 0.0053);Gain of methylation at E1182 (P = 0.0053);.;
MVP		0.71
MPC		0.62
ClinPred		0.96	D
GERP RS		5.1
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.46
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs1398515136; hg19: chr17-2595183;