3-33826497-A-C

Variant names:

• chr3-33826497-A-C
• NM_013374.6:c.634A>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_013374.6(PDCD6IP):​c.634A>C​(p.Ile212Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDCD6IP NM_013374.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.08

Genes affected

PDCD6IP (HGNC:8766): (programmed cell death 6 interacting protein) This gene encodes a protein that functions within the ESCRT pathway in the abscission stage of cytokinesis, in intralumenal endosomal vesicle formation, and in enveloped virus budding. Studies using mouse cells have shown that overexpression of this protein can block apoptosis. In addition, the product of this gene binds to the product of the PDCD6 gene, a protein required for apoptosis, in a calcium-dependent manner. This gene product also binds to endophilins, proteins that regulate membrane shape during endocytosis. Overexpression of this gene product and endophilins results in cytoplasmic vacuolization, which may be partly responsible for the protection against cell death. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. Related pseudogenes have been identified on chromosome 15. [provided by RefSeq, Jan 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a mutagenesis_site Does not support cytokinesis; loss of normal midbody formation; loss of CHMP4A-, CHMP4B- and CHMP4C-binding in a yeast two-hybrid assay; impairs rescue of PTAP-type L domain-deficient HIV-1 p6; no effect on localization to the midbody. (size 0) in uniprot entity PDC6I_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26940048).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDCD6IP	NM_013374.6	c.634A>C	p.Ile212Leu	missense_variant	Exon 6 of 18	ENST00000307296.8	NP_037506.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDCD6IP	ENST00000307296.8	c.634A>C	p.Ile212Leu	missense_variant	Exon 6 of 18	1	NM_013374.6	ENSP00000307387.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.634A>C (p.I212L) alteration is located in exon 6 (coding exon 6) of the PDCD6IP gene. This alteration results from a A to C substitution at nucleotide position 634, causing the isoleucine (I) at amino acid position 212 to be replaced by a leucine (L). 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	Uncertain	0.49
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.042	T;.
Eigen	Benign	-0.17
Eigen_PC	Benign	0.064
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.93	L;L
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.10
Sift	Uncertain	0.024	D;D
Sift4G	Uncertain	0.043	D;D
Polyphen		0.0050	B;.
Vest4		0.46
MutPred		0.47		Gain of ubiquitination at K215 (P = 0.123);Gain of ubiquitination at K215 (P = 0.123);
MVP		0.33
MPC		0.32
ClinPred		0.85	D
GERP RS		5.7
Varity_R		0.63
gMVP		0.053

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-33867989;