chr17-80994641-G-C

Variant names:

• chr17-80994641-G-C
• rs1314960544
• NM_024591.5:c.124G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024591.5(CHMP6):​c.124G>C​(p.Glu42Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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: 4.15
• Publications: 1 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28397086).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHMP6	NM_024591.5	c.124G>C	p.Glu42Gln	missense_variant	Exon 2 of 8	ENST00000325167.9	NP_078867.2
CHMP6	XM_005257668.1	c.124G>C	p.Glu42Gln	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.124G>C	p.Glu42Gln	missense_variant	Exon 2 of 8	1	NM_024591.5	ENSP00000317468.5
CHMP6	ENST00000572778.5	c.61G>C	p.Glu21Gln	missense_variant	Exon 1 of 6	2		ENSP00000461098.1
CHMP6	ENST00000572525.5	c.-135G>C		5_prime_UTR_variant	Exon 2 of 8	3		ENSP00000460389.1
CHMP6	ENST00000571457.1	c.-3G>C		upstream_gene_variant		3		ENSP00000461238.1

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

Mar 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.124G>C (p.E42Q) alteration is located in exon 2 (coding exon 2) of the CHMP6 gene. This alteration results from a G to C substitution at nucleotide position 124, causing the glutamic acid (E) at amino acid position 42 to be replaced by a glutamine (Q). 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	0.15
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;.
Eigen	Benign	-0.0035
Eigen_PC	Benign	0.096
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.4	L;.
PhyloP100		4.1
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.8	N;.
REVEL	Benign	0.14
Sift	Benign	0.088	T;.
Sift4G	Benign	0.088	T;D
Polyphen		0.43	B;.
Vest4		0.33
MutPred		0.45		Gain of solvent accessibility (P = 0.5843);.;
MVP		0.52
MPC		0.12
ClinPred		0.60	D
GERP RS		3.4
PromoterAI		0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.25

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

dbSNP: rs1314960544; hg19: chr17-78968441;