17-2691889-C-G

Variant names:

• chr17-2691889-C-G
• rs1398515136
• NM_001366661.1:c.3661G>C

Variant summary

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

The NM_001366661.1(CLUH):​c.3661G>C​(p.Glu1221Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000133 in 150,470 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1221K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CLUH NM_001366661.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• Publications: 1 publications found

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

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

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366661.1. 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
	CLUH	NM_001366661.1	MANE Select	c.3661G>C	p.Glu1221Gln	missense	Exon 24 of 26	NP_001353590.1	A0A494C0R8
	CLUH	NM_015229.4		c.3658G>C	p.Glu1220Gln	missense	Exon 24 of 26	NP_056044.4
	CLUH	NM_001366662.1		c.3544G>C	p.Glu1182Gln	missense	Exon 24 of 26	NP_001353591.1	O75153

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLUH	ENST00000651024.2	MANE Select	c.3661G>C	p.Glu1221Gln	missense	Exon 24 of 26	ENSP00000498679.1	A0A494C0R8
	CLUH	ENST00000574210.5	TSL:1	n.985G>C		non_coding_transcript_exon	Exon 8 of 9
	CLUH	ENST00000876318.1		c.3679G>C	p.Glu1227Gln	missense	Exon 24 of 26	ENSP00000546377.1

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150470 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000297

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1384520 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 683284

African (AFR) AF: 0.00 AC: 0 AN: 31364

American (AMR) AF: 0.00 AC: 0 AN: 35536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24992

East Asian (EAS) AF: 0.00 AC: 0 AN: 35440

South Asian (SAS) AF: 0.00 AC: 0 AN: 79110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39684

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5226

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1075656

Other (OTH) AF: 0.00 AC: 0 AN: 57512

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150470 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73444

African (AFR) AF: 0.00 AC: 0 AN: 40988

American (AMR) AF: 0.00 AC: 0 AN: 15122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3428

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000297 AC: 2 AN: 67438

Other (OTH) AF: 0.00 AC: 0 AN: 2046

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.054	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.9
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.57
Sift	Uncertain	0.026	D
Sift4G	Benign	0.074	T
Polyphen		0.91	P
Vest4		0.64
MutPred		0.52		Loss of ubiquitination at K1177 (P = 0.0796)
MVP		0.69
MPC		0.67
ClinPred		0.94	D
GERP RS		5.1
Varity_R		0.31
gMVP		0.65
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1398515136; hg19: chr17-2595183; COSMIC: COSV70929867; COSMIC: COSV70929867;