chr19-44871900-G-C

Position:

• chr19-44871900-G-C

Variant summary

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

The NM_001042724.2(NECTIN2):​c.526G>C​(p.Asp176His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,614,140 control chromosomes in the GnomAD database, including 86 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 0.0012 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0021 (82 hom.)
• Consequence: NECTIN2 NM_001042724.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 2.01

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041297674).
• BP6: Variant 19-44871900-G-C is Benign according to our data. Variant chr19-44871900-G-C is described in ClinVar as [Benign]. Clinvar id is 712411.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0012 (183/152250) while in subpopulation SAS AF= 0.0371 (179/4822). AF 95% confidence interval is 0.0327. There are 4 homozygotes in gnomad4. There are 133 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NECTIN2	NM_001042724.2	c.526G>C	p.Asp176His	missense_variant	3/9	ENST00000252483.10	NP_001036189.1
NECTIN2	NM_002856.3	c.526G>C	p.Asp176His	missense_variant	3/6		NP_002847.1
NECTIN2	XM_047439169.1	c.526G>C	p.Asp176His	missense_variant	3/6		XP_047295125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NECTIN2	ENST00000252483.10	c.526G>C	p.Asp176His	missense_variant	3/9	1	NM_001042724.2	ENSP00000252483	P3
NECTIN2	ENST00000252485.8	c.526G>C	p.Asp176His	missense_variant	3/6	1		ENSP00000252485	A2
NECTIN2	ENST00000591581.1	c.49G>C	p.Asp17His	missense_variant	1/4	2		ENSP00000465587

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 186 AN: 152130 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0377

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00440 AC: 1103 AN: 250720 Hom.: 34 AF XY: 0.00591 AC XY: 801 AN XY: 135636

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0352

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00208 AC: 3044 AN: 1461890 Hom.: 82 Cov.: 32 AF XY: 0.00298 AC XY: 2164 AN XY: 727244

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0330

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.00248

GnomAD4 genome AF: 0.00120 AC: 183 AN: 152250 Hom.: 4 Cov.: 31 AF XY: 0.00179 AC XY: 133 AN XY: 74436

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0371

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000384 Hom.: 1

Bravo AF: 0.000238

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00511 AC: 620

Asia WGS AF: 0.0200 AC: 68 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

NECTIN2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	.;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.79	T;T
MetaRNN	Benign	0.0041	T;T
MetaSVM	Benign	-0.62	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.093
Sift	Benign	0.086	T;D
Sift4G	Uncertain	0.013	D;T
Polyphen		0.82	P;P
Vest4		0.27
MVP		0.62
MPC		1.1
ClinPred		0.038	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.054
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146534542; hg19: chr19-45375157; COSMIC: COSV52977442; COSMIC: COSV52977442;