chr17-80994672-T-C

Variant names:

• chr17-80994672-T-C
• NM_024591.5:c.155T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024591.5(CHMP6):​c.155T>C​(p.Leu52Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHMP6 NM_024591.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.53
• Publications: 0 publications found

Genes affected

CHMP6 (HGNC:25675): (charged multivesicular body protein 6) This gene encodes a member of the chromatin-modifying protein/charged multivesicular body protein family. Proteins in this family are part of the ESCRT-III (endosomal sorting complex required for transport III) which degrades surface receptors, and in biosynthesis of endosomes. [provided by RefSeq, Mar 2012]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHMP6	NM_024591.5	c.155T>C	p.Leu52Pro	missense_variant	Exon 2 of 8	ENST00000325167.9	NP_078867.2
CHMP6	XM_005257668.1	c.155T>C	p.Leu52Pro	missense_variant	Exon 2 of 7		XP_005257725.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHMP6	ENST00000325167.9	c.155T>C	p.Leu52Pro	missense_variant	Exon 2 of 8	1	NM_024591.5	ENSP00000317468.5
CHMP6	ENST00000572778.5	c.92T>C	p.Leu31Pro	missense_variant	Exon 1 of 6	2		ENSP00000461098.1
CHMP6	ENST00000571457.1	c.29T>C	p.Leu10Pro	missense_variant	Exon 1 of 7	3		ENSP00000461238.1
CHMP6	ENST00000572525.5	c.-104T>C		5_prime_UTR_variant	Exon 2 of 8	3		ENSP00000460389.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.155T>C (p.L52P) alteration is located in exon 2 (coding exon 2) of the CHMP6 gene. This alteration results from a T to C substitution at nucleotide position 155, causing the leucine (L) at amino acid position 52 to be replaced by a proline (P). 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Pathogenic	3.6	H;.;.
PhyloP100		4.5
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.2	D;.;.
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.96
MutPred		0.51		Loss of stability (P = 0.0121);.;.;
MVP		0.82
MPC		0.50
ClinPred		1.0	D
GERP RS		4.4
PromoterAI		-0.0065	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95
gMVP		0.80

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

Other links and lift over

hg19: chr17-78968472;