rs4807

Positions:

• chr2-10790777-T-A
• chr2-10790777-T-C
• chr2-10790777-T-G

Variant summary

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

The NM_005742.4(PDIA6):​c.641A>T​(p.Lys214Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. K214R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PDIA6 NM_005742.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.15

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDIA6	NM_005742.4	c.641A>T	p.Lys214Ile	missense_variant	7/13	ENST00000272227.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDIA6	ENST00000272227.8	c.641A>T	p.Lys214Ile	missense_variant	7/13	1	NM_005742.4	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461834 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727222

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.;.;.;.;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;.;D;D
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.85	L;.;.;.;.;.
MutationTaster	Benign	6.0e-10	P;P;P;P;P
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-7.2	D;D;.;D;D;D
REVEL	Benign	0.25
Sift	Uncertain	0.0010	D;D;.;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D
Polyphen		0.50	P;.;B;B;.;.
Vest4		0.59
MutPred		0.60		Loss of disorder (P = 0.0011);.;.;.;.;.;
MVP		0.38
MPC		0.89
ClinPred		0.99	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.84

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: rs4807; hg19: chr2-10930903;