2-10789830-G-T

Position:

• chr2-10789830-G-T

Variant summary

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

The NM_005742.4(PDIA6):​c.759C>A​(p.Asp253Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 32)
• Consequence: PDIA6 NM_005742.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0480

Genes affected

PDIA6 (HGNC:30168): (protein disulfide isomerase family A member 6) This gene encodes a member of the disulfide isomerase (PDI) family of endoplasmic reticulum (ER) proteins that catalyze protein folding and thiol-disulfide interchange reactions. The encoded protein has an N-terminal ER-signal sequence, two catalytically active thioredoxin (TRX) domains, a TRX-like domain, and a C-terminal ER-retention sequence. This protein inhibits the aggregation of misfolded proteins and exhibits both isomerase and chaperone activity. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2016]

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=0.1487301).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDIA6	NM_005742.4	c.759C>A	p.Asp253Glu	missense_variant	8/13	ENST00000272227.8	NP_005733.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDIA6	ENST00000272227.8	c.759C>A	p.Asp253Glu	missense_variant	8/13	1	NM_005742.4	ENSP00000272227.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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

Oct 25, 2024

The c.759C>A (p.D253E) alteration is located in exon 8 (coding exon 8) of the PDIA6 gene. This alteration results from a C to A substitution at nucleotide position 759, causing the aspartic acid (D) at amino acid position 253 to be replaced by a glutamic acid (E). 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	0.14
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.13
DANN	Benign	0.96
DEOGEN2	Benign	0.015	T;.;.;.;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.87	D;D;D;.;D;D
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.15	T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-0.020	N;.;.;.;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.5	N;N;.;N;N;N
REVEL	Benign	0.065
Sift	Benign	0.36	T;T;.;T;T;T
Sift4G	Benign	0.65	T;T;T;T;T;T
Polyphen		0.0	B;.;B;B;.;.
Vest4		0.19
MutPred		0.45		Gain of disorder (P = 0.1854);.;.;.;.;.;
MVP		0.099
MPC		0.21
ClinPred		0.12	T
GERP RS		-7.2
Varity_R		0.30
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr2-10929956; COSMIC: COSV55352551; COSMIC: COSV55352551;