rs2274515

Variant names:

• chr6-42965788-C-A
• rs2274515
• ENST00000244546.4:c.2117G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-42965788-C-A
• chr6-42965788-C-G
• chr6-42965788-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000244546.4(PEX6):​c.2117G>T​(p.Cys706Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. C706Y) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PEX6 ENST00000244546.4 missense, splice_region
• Scores: Splicing: ADA: 0.0007229
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.32
• Publications: 0 publications found

Genes affected

PEX6 (HGNC:8859): (peroxisomal biogenesis factor 6) This gene encodes a member of the AAA (ATPases associated with diverse cellular activities) family of ATPases. This member is a predominantly cytoplasmic protein, which plays a direct role in peroxisomal protein import and is required for PTS1 (peroxisomal targeting signal 1, a C-terminal tripeptide of the sequence ser-lys-leu) receptor activity. Mutations in this gene cause peroxisome biogenesis disorders of complementation group 4 and complementation group 6. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

PEX6 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 4A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health
• peroxisome biogenesis disorder 4B

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Heimler syndrome 2

  Inheritance: AR Classification: MODERATE Submitted by: G2P
• autosomal recessive cerebellar ataxia-blindness-deafness syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX6	NM_000287.4	c.2364G>T	p.Val788Val	splice_region_variant, synonymous_variant	Exon 13 of 17	ENST00000304611.13	NP_000278.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX6	ENST00000244546.4	c.2117G>T	p.Cys706Phe	missense_variant, splice_region_variant	Exon 11 of 15	1		ENSP00000244546.4
PEX6	ENST00000304611.13	c.2364G>T	p.Val788Val	splice_region_variant, synonymous_variant	Exon 13 of 17	1	NM_000287.4	ENSP00000303511.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	12
DANN	Benign	0.96
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.38	T
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.42	D
PhyloP100		1.3
PROVEAN	Benign	0.28	N
REVEL	Uncertain	0.30
Sift	Benign	0.066	T
Sift4G	Benign	0.098	T
Vest4		0.70
MutPred		0.48		Gain of helix (P = 0.0143);
MVP		0.96
ClinPred		0.28	T
GERP RS		3.1
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00072
dbscSNV1_RF	Benign	0.096
SpliceAI score (max)		0.040		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: rs2274515; hg19: chr6-42933526;