19-44650057-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006505.5(PVR):c.676G>A(p.Glu226Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000784 in 1,554,248 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00074 (16 hom.)
• Consequence: PVR NM_006505.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.37

Genes affected

PVR (HGNC:9705): (PVR cell adhesion molecule) The protein encoded by this gene is a transmembrane glycoprotein belonging to the immunoglobulin superfamily. The external domain mediates cell attachment to the extracellular matrix molecule vitronectin, while its intracellular domain interacts with the dynein light chain Tctex-1/DYNLT1. The gene is specific to the primate lineage, and serves as a cellular receptor for poliovirus in the first step of poliovirus replication. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

CEACAM16-AS1 (HGNC:55317): (CEACAM16, CEACAM19 and PVR antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008191377).
• BP6: Variant 19-44650057-G-A is Benign according to our data. Variant chr19-44650057-G-A is described in ClinVar as [Benign]. Clinvar id is 3034003.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0012 (183/152308) while in subpopulation EAS AF= 0.0276 (143/5190). AF 95% confidence interval is 0.0239. There are 2 homozygotes in gnomad4. There are 109 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PVR	NM_006505.5	c.676G>A	p.Glu226Lys	missense_variant	3/8	ENST00000425690.8
PVR	NM_001135770.4	c.676G>A	p.Glu226Lys	missense_variant	3/6
PVR	NM_001135768.3	c.676G>A	p.Glu226Lys	missense_variant	3/8
PVR	NM_001135769.3	c.676G>A	p.Glu226Lys	missense_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PVR	ENST00000425690.8	c.676G>A	p.Glu226Lys	missense_variant	3/8	1	NM_006505.5	P2
CEACAM16-AS1	ENST00000662585.1	n.476-17438C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 183 AN: 152190 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0275

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00285 AC: 571 AN: 200178 Hom.: 9 AF XY: 0.00250 AC XY: 266 AN XY: 106376

Gnomad AFR exome AF: 0.000446

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0316

Gnomad SAS exome AF: 0.000739

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000432

Gnomad OTH exome AF: 0.00193

GnomAD4 exome AF: 0.000739 AC: 1036 AN: 1401940 Hom.: 16 Cov.: 31 AF XY: 0.000730 AC XY: 504 AN XY: 690746

Gnomad4 AFR exome AF: 0.000189

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0188

Gnomad4 SAS exome AF: 0.00115

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000721

Gnomad4 OTH exome AF: 0.00222

GnomAD4 genome AF: 0.00120 AC: 183 AN: 152308 Hom.: 2 Cov.: 31 AF XY: 0.00146 AC XY: 109 AN XY: 74474

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0276

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00116 Hom.: 4

Bravo AF: 0.00144

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00224 AC: 271

Asia WGS AF: 0.0190 AC: 67 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PVR-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 13, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.044	T;.;.;T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.97	D;D;D;D
MetaRNN	Benign	0.0082	T;T;T;T
MetaSVM	Uncertain	-0.16	T
MutationTaster	Benign	0.82	N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.0	D;D;D;D
REVEL	Uncertain	0.39
Sift	Benign	0.081	T;T;T;T
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		0.99, 1.0	.;D;D;.
Vest4		0.29
MVP		0.86
MPC		1.2
ClinPred		0.046	T
GERP RS		4.7
gMVP		0.34

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: rs139528439; hg19: chr19-45153329; COSMIC: COSV51822134; COSMIC: COSV51822134;