chr19-44873997-G-A

Position:

• chr19-44873997-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001042724.2(NECTIN2):​c.857G>A​(p.Arg286His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,613,848 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (10 hom.)
• Consequence: NECTIN2 NM_001042724.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.31

Genes affected

NECTIN2 (HGNC:9707): (nectin cell adhesion molecule 2) This gene encodes a single-pass type I membrane glycoprotein with two Ig-like C2-type domains and an Ig-like V-type domain. This protein is one of the plasma membrane components of adherens junctions. It also serves as an entry for certain mutant strains of herpes simplex virus and pseudorabies virus, and it is involved in cell to cell spreading of these viruses. Variations in this gene have been associated with differences in the severity of multiple sclerosis. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0073524415).
• BP6: Variant 19-44873997-G-A is Benign according to our data. Variant chr19-44873997-G-A is described in ClinVar as [Benign]. Clinvar id is 727455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00501 (763/152166) while in subpopulation AFR AF= 0.0171 (709/41514). AF 95% confidence interval is 0.016. There are 8 homozygotes in gnomad4. There are 343 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NECTIN2	NM_001042724.2	c.857G>A	p.Arg286His	missense_variant	4/9	ENST00000252483.10
NECTIN2	NM_002856.3	c.857G>A	p.Arg286His	missense_variant	4/6
NECTIN2	XM_047439169.1	c.857G>A	p.Arg286His	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NECTIN2	ENST00000252483.10	c.857G>A	p.Arg286His	missense_variant	4/9	1	NM_001042724.2	P3
NECTIN2	ENST00000252485.8	c.857G>A	p.Arg286His	missense_variant	4/6	1		A2
NECTIN2	ENST00000591581.1	c.380G>A	p.Arg127His	missense_variant	2/4	2
NECTIN2	ENST00000587386.1	n.56G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00500 AC: 760 AN: 152048 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00243

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00154 AC: 386 AN: 251202 Hom.: 2 AF XY: 0.00119 AC XY: 161 AN XY: 135744

Gnomad AFR exome AF: 0.0184

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000622 AC: 909 AN: 1461682 Hom.: 10 Cov.: 31 AF XY: 0.000558 AC XY: 406 AN XY: 727144

Gnomad4 AFR exome AF: 0.0170

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.00188

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000944

Gnomad4 OTH exome AF: 0.00174

GnomAD4 genome AF: 0.00501 AC: 763 AN: 152166 Hom.: 8 Cov.: 32 AF XY: 0.00461 AC XY: 343 AN XY: 74390

Gnomad4 AFR AF: 0.0171

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00105 Hom.: 3

Bravo AF: 0.00584

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0177 AC: 78

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00186 AC: 226

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 30, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	.;T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.84	T;T
MetaRNN	Benign	0.0074	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.93	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.068
Sift	Benign	0.39	T;T
Sift4G	Benign	0.094	T;T
Polyphen		0.31	B;B
Vest4		0.29
MVP		0.11
MPC		0.52
ClinPred		0.0074	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.017
gMVP		0.53

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: rs149575863; hg19: chr19-45377254; COSMIC: COSV52976292; COSMIC: COSV52976292;