17-2694185-A-G

Variant names:

• chr17-2694185-A-G
• rs1334650747
• NM_001366661.1:c.3029T>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001366661.1(CLUH):​c.3029T>C​(p.Val1010Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,014 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1010I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CLUH NM_001366661.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.88

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38240737).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLUH	NM_001366661.1	c.3029T>C	p.Val1010Ala	missense_variant	Exon 18 of 26	ENST00000651024.2	NP_001353590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLUH	ENST00000651024.2	c.3029T>C	p.Val1010Ala	missense_variant	Exon 18 of 26		NM_001366661.1	ENSP00000498679.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461014 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726746

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2912T>C (p.V971A) alteration is located in exon 18 (coding exon 17) of the CLUH gene. This alteration results from a T to C substitution at nucleotide position 2912, causing the valine (V) at amino acid position 971 to be replaced by an alanine (A). 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	0.50
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T;T;T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T;.;.
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.9	L;L;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.1	D;.;.
REVEL	Uncertain	0.32
Sift	Benign	0.19	T;.;.
Sift4G	Benign	0.33	T;T;.
Polyphen		0.0020	B;B;.
Vest4		0.86
MutPred		0.40		Gain of disorder (P = 0.0548);Gain of disorder (P = 0.0548);.;
MVP		0.71
MPC		0.37
ClinPred		0.82	D
GERP RS		5.7
Varity_R		0.26
gMVP		0.70

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

LitVar

Other links and lift over

dbSNP: rs1334650747; hg19: chr17-2597479;