17-80995081-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024591.5(CHMP6):c.236A>C(p.Asn79Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CHMP6 NM_024591.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.17

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14867294).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHMP6	NM_024591.5	c.236A>C	p.Asn79Thr	missense_variant	3/8	ENST00000325167.9
CHMP6	XM_005257668.1	c.236A>C	p.Asn79Thr	missense_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHMP6	ENST00000325167.9	c.236A>C	p.Asn79Thr	missense_variant	3/8	1	NM_024591.5	P1
CHMP6	ENST00000572778.5	c.173A>C	p.Asn58Thr	missense_variant	2/6	2
CHMP6	ENST00000571457.1	c.110A>C	p.Asn37Thr	missense_variant	2/7	3
CHMP6	ENST00000572525.5	c.-23A>C		5_prime_UTR_variant	3/8	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450432 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 720272

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: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Dec 28, 2022

The c.236A>C (p.N79T) alteration is located in exon 3 (coding exon 3) of the CHMP6 gene. This alteration results from a A to C substitution at nucleotide position 236, causing the asparagine (N) at amino acid position 79 to be replaced by a threonine (T). 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	0.087
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	11
Dann	Benign	0.77
DEOGEN2	Benign	0.23	T;.;.
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.77
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.5	N;.;.
REVEL	Benign	0.11
Sift	Benign	0.55	T;.;.
Sift4G	Benign	0.46	T;T;T
Polyphen		0.098	B;.;.
Vest4		0.31
MutPred		0.39		Gain of phosphorylation at N79 (P = 0.0424);.;.;
MVP		0.57
MPC		0.068
ClinPred		0.12	T
GERP RS		-0.80
Varity_R		0.16
gMVP		0.35

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: rs1283236782; hg19: chr17-78968881;