2-10790777-T-C

Variant names:

• chr2-10790777-T-C
• rs4807
• NM_005742.4:c.641A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005742.4(PDIA6):​c.641A>G​(p.Lys214Arg) variant causes a missense change. The variant allele was found at a frequency of 0.275 in 1,613,324 control chromosomes in the GnomAD database, including 63,503 homozygotes. 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: 𝑓 0.25 (5302 hom., cov: 33)
  • Exomes 𝑓: 0.28 (58201 hom.)
• Consequence: PDIA6 NM_005742.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.15
• Publications: 44 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026494265).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.38 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005742.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDIA6	NM_005742.4	MANE Select	c.641A>G	p.Lys214Arg	missense	Exon 7 of 13	NP_005733.1	Q15084-1
	PDIA6	NM_001282704.2		c.797A>G	p.Lys266Arg	missense	Exon 9 of 15	NP_001269633.1	Q15084-2
	PDIA6	NM_001282705.2		c.785A>G	p.Lys262Arg	missense	Exon 8 of 14	NP_001269634.1	Q15084-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDIA6	ENST00000272227.8	TSL:1 MANE Select	c.641A>G	p.Lys214Arg	missense	Exon 7 of 13	ENSP00000272227.4	Q15084-1
	PDIA6	ENST00000404371.6	TSL:2	c.797A>G	p.Lys266Arg	missense	Exon 9 of 15	ENSP00000385385.2	Q15084-2
	PDIA6	ENST00000617249.4	TSL:5	c.797A>G	p.Lys266Arg	missense	Exon 8 of 14	ENSP00000481892.1	Q15084-2

Frequencies

GnomAD3 genomes AF: 0.247 AC: 37626 AN: 152068 Hom.: 5302 Cov.: 33

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.344

Gnomad ASJ AF: 0.349

Gnomad EAS AF: 0.394

Gnomad SAS AF: 0.352

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.284

GnomAD2 exomes AF: 0.306 AC: 76928 AN: 251386 AF XY: 0.307

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.422

Gnomad ASJ exome AF: 0.340

Gnomad EAS exome AF: 0.381

Gnomad FIN exome AF: 0.242

Gnomad NFE exome AF: 0.282

Gnomad OTH exome AF: 0.315

GnomAD4 exome AF: 0.278 AC: 405574 AN: 1461138 Hom.: 58201 Cov.: 33 AF XY: 0.280 AC XY: 203710 AN XY: 726918

African (AFR) AF: 0.122 AC: 4073 AN: 33470

American (AMR) AF: 0.406 AC: 18169 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.335 AC: 8760 AN: 26128

East Asian (EAS) AF: 0.332 AC: 13192 AN: 39686

South Asian (SAS) AF: 0.346 AC: 29841 AN: 86214

European-Finnish (FIN) AF: 0.243 AC: 12998 AN: 53412

Middle Eastern (MID) AF: 0.349 AC: 2011 AN: 5768

European-Non Finnish (NFE) AF: 0.269 AC: 299174 AN: 1111372

Other (OTH) AF: 0.288 AC: 17356 AN: 60368

GnomAD4 genome AF: 0.247 AC: 37634 AN: 152186 Hom.: 5302 Cov.: 33 AF XY: 0.253 AC XY: 18799 AN XY: 74390

African (AFR) AF: 0.125 AC: 5186 AN: 41532

American (AMR) AF: 0.344 AC: 5256 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 1213 AN: 3472

East Asian (EAS) AF: 0.394 AC: 2039 AN: 5176

South Asian (SAS) AF: 0.353 AC: 1703 AN: 4824

European-Finnish (FIN) AF: 0.243 AC: 2570 AN: 10576

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.274 AC: 18634 AN: 67998

Other (OTH) AF: 0.284 AC: 600 AN: 2110

Alfa AF: 0.274 Hom.: 20653

Bravo AF: 0.251

TwinsUK AF: 0.265 AC: 984

ALSPAC AF: 0.269 AC: 1036

ESP6500AA AF: 0.124 AC: 547

ESP6500EA AF: 0.285 AC: 2453

ExAC AF: 0.298 AC: 36157

Asia WGS AF: 0.359 AC: 1246 AN: 3478

EpiCase AF: 0.292

EpiControl AF: 0.295

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.044
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.97	L
PhyloP100		5.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.093
Sift	Benign	0.068	T
Sift4G	Benign	0.16	T
Polyphen		0.0030	B
Vest4		0.14
MPC		0.19
ClinPred		0.056	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.68
Mutation Taster		=87/13	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4807; hg19: chr2-10930903; COSMIC: COSV55349252;